Drug-coated balloon catheters for body lumens

ABSTRACT

Various embodiments disclosed relate to drug-coated balloon catheters for treating strictures in body lumens and methods of using the same. A drug-coated balloon catheter for delivering a therapeutic agent to a target site of a body lumen stricture includes an elongated balloon having a main diameter. The balloon catheter includes a coating layer overlying an exterior surface of the balloon. The coating layer includes one or more water-soluble additives and an initial drug load of a therapeutic agent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.16/986,683, Filed Aug. 6, 2020, which is a division of U.S. patentapplication Ser. No. 16/135,436, filed Sep. 19, 2018, which is acontinuation-in-part of International Application No. PCT/US2018/03108filed May 4, 2018, which claims the benefit of priority to U.S.Provisional Patent Application Ser. No. 62/502,212 filed May 5, 2017.This application is also a continuation-in-part of U.S. patentapplication Ser. No. 15/568,614 filed Oct. 23, 2017, which is a U.S.National Stage Filing under 35 U.S.C. 371 from International ApplicationNo. PCT/US2016/028652 filed Apr. 21, 2016, which claims the benefit ofpriority to U.S. Provisional Patent Application Ser. No. 62/152,559filed Apr. 24, 2015. This application is also a continuation-in-part ofU.S. patent application Ser. No. 14/438,327 filed Apr. 24, 2015, whichis a U.S. National Stage Filing under 35 U.S.C. 371 from InternationalApplication No. PCT/US2013/064842 filed Oct. 14, 2013, which claims thebenefit of priority to U.S. Provisional Patent Application Ser. No.61/795,790 filed Oct. 26, 2012. The disclosure of each of theseapplications are incorporated herein by reference in their entirety.

BACKGROUND

Benign prostatic hyperplasia is a non-cancerous enlargement of theprostate gland, affecting more than 50% percent of men over the age of60. The prostate early in life is the size and shape of a walnut andweighs about 20 grams. Prostate enlargement appears to be a normalprocess. With age, the prostate gradually increases in size to twice ormore its normal size. As the prostate grows, it presses against andnarrows the urethra, causing prostatic urethra compression and urinaryobstruction that makes voiding difficult or impossible.

Male urethral stricture disease occurs at a rate as high as 0.6% in somepopulations. Urethral stricture diseases appear to be more common in theelderly population. The patients with the strictures experience moderateto severe complications, such as lower urinary tract voiding symptoms orurinary retention, recurrent urinary tract infection and the need forrepeat urethral procedures such as dilation, urethrotomy, orurethroplasty.

Ureteral strictures of the upper urinary tract are either congenital oracquired. Congenital ureteral strictures are most commonly located atthe ureteropelvic junction. Most of ureteral strictures are acquired andusually are iatrogenic. The most common etiology of the ureteralstrictures is injury during endoscopic, open, or laparoscopic surgicalprocedures.

Strictures in the digestive body lumen or the gastrointestinal tractsinclude esophageal strictures, achalasia strictures, biliary strictures,stomach strictures, small intestine strictures, duodenum strictures,jejunum strictures, ileum strictures, colon strictures, rectumstrictures, and large intestine strictures. The type of diseaseclassifies a stricture into benign or malignant.

A biliary stricture, also referred to as a bile duct stricture, occurswhen the bile duct gets smaller or narrower. The bile duct is the tubethat takes bile from the liver to the small intestine. When the bileduct becomes narrow, it makes it difficult for food to digest. Biliarystrictures can be caused by any injuries to the bile duct, swelling,pancreatitis, intestinal injuries, and cancers in the bile duct orpancreas. The symptoms of the biliary stricture include pain, chills andfever, itching, and nausea or vomiting.

Esophageal strictures are a problem commonly encountered ingastroenterological medicine and can be caused by malignant or benignlesions. Dysphagia is the symptom experienced by all patients. Most ofthese patients require palliative treatment to relieve the dysphagia.

Gastrointestinal strictures are a narrowing of a section of theintestine that causes problems by slowing or blocking the movement offood through the area. The strictures are caused by recurrentinflammations, cancer, Crohn's disease, and ulcerative colitis. Thestrictures include esophageal strictures, achalasia strictures,strictures in stents, biliary strictures, stomach strictures, smallintestine strictures, duodenum strictures, jejunum strictures, ileumstrictures, colon strictures, rectum strictures, and large intestinestrictures.

Chronic obstructive pulmonary disease (COPD) is a term used to classifytwo major airflow obstruction disorders: chronic bronchitis andemphysema. Approximately 16 million Americans have COPD, 80-90% of themwere smokers throughout much of their lives. COPD is a leading cause ofdeath in the U.S. Chronic bronchitis is inflammation of the bronchialairways. The bronchial airways connect the trachea with the lungs. Wheninflamed, the bronchial tubes secrete mucus, causing a chronic cough.Emphysema is an over-inflation of the alveoli, or air sacs in the lungs.This condition causes shortness of breath.

Asthma is a chronic respiratory disease characterized by inflammation ofthe airways, excess mucus production and airway hyper-responsiveness,and a condition in which airways narrow excessively or too easilyrespond to a stimulus. Asthma episodes or attacks cause narrowing of theairways, which make breathing difficult. Asthma attacks can have asignificant impact on a patient's life, limiting participation in manyactivities. In severe cases, asthma attacks can be life threatening.Presently, there is no known cure for asthma.

Chronic sinusitis is an inflammation of the membrane lining of one ormore paranasal sinuses. Chronic sinusitis lasts longer than three weeksand often continues for months. In cases of chronic sinusitis, there isusually tissue damage. According to the Center for Disease Control(CDC), thirty-seven million cases of chronic sinusitis are reportedannually.

SUMMARY OF THE INVENTION

In various embodiments, the present invention provides a drug-coatedballoon catheter for delivering a therapeutic agent to a target site ofa body lumen stricture. The body lumen strictures can include benignprostatic hyperplasia (BPH), urethral strictures, ureteral strictures,prostate cancer, esophageal strictures, achalasia strictures, stricturesin stents, biliary tract strictures, stomach strictures, small intestinestrictures, duodenum strictures, jejunum strictures, ileum strictures,colon strictures, rectum strictures, and large intestine strictures,asthma and chronic obstructive pulmonary disease (COPD). The ballooncatheter includes an elongated balloon having a main diameter. Theballoon catheter also includes a coating layer overlying an exteriorsurface of the balloon, wherein the coating layer includes one or morewater-soluble additives and an initial drug load of a therapeutic agent.

In various embodiments, the present invention provides a method fortreating a body lumen stricture. The method includes inserting a ballooncatheter into a target site in the body lumen. The method optionallyincludes, prior to, during, or after the insertion of the balloon to thetarget site, flushing the body lumen with water, saline solution, or awater solution including at least one water soluble additive. Theballoon catheter also includes a coating layer overlying an exteriorsurface of the balloon. The coating layer includes one or morewater-soluble additives and an initial drug load of a therapeutic agent.The method includes inflating the balloon until the coating layercontacts walls of the body lumen at the target site and the balloonachieves an inflated balloon diameter for an inflation period. Feature(a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or(a) and (b) and (c), are present: (a) the ratio of the inflated balloondiameter to a normative body lumen diameter at the target site is about1.0 to about 20; or (b) the inflating comprises inflating the balloon toa pressure equal to or greater than a nominal pressure of the ballooncatheter, and the stretch ratio of a nominal diameter of the ballooncatheter to a normative body lumen diameter at the target site is about1.0 to about 20; or (c) the inflating comprises inflating to a pressuregreater than the nominal pressure of the balloon catheter, and thenominal diameter of the balloon catheter is less than the inflatedballoon diameter; or (d) a combination of (a), (b), and (c). The methodincludes deflating the balloon after the inflation period. The methodalso includes withdrawing the balloon catheter from the body lumen.

In various embodiments, the present invention provides a method fortreating a body lumen stricture. The method includes inserting a scopesuch as a cystoscope into a body lumen. The method includes inserting aballoon catheter with a drug coating into the body lumen. The methodincludes inflating to the balloon catheter to an initial pressure ofbetween 0.5 atm and 1.5 atm and maintaining the initial pressure untilthe pressure no longer drops. The method includes inflating to a nexthigher pressure at least 0.5 atm to 1.5 atm above the initial pressureand maintaining the next higher pressure until the pressure inside theballoon no longer drops, and repeating this step until the lumen isdilated to a desired diameter. The method includes keeping the ballooninflated for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes torelease the drug into tissue and to prevent bleeding. The methodincludes deflating the balloon catheter. The method also includeswithdrawing the scope and balloon catheter from the body lumen.

Various embodiments of the present invention provide a method fortreatment of a body lumen stricture. The method includes inserting aflexible scope to the body lumen stricture. The method includesinserting a balloon catheter in the body lumen stricture side by sidewith the scope. The method includes inflating the balloon catheterslowly to prevent balloon migration, such as by optionally inflating toan initial pressure between 0.5 atm and 1.5 atm and maintaining theinitial pressure until the pressure no longer drops, and inflating to ahigher pressure 0.5 atm to 1.5 atm above the initial pressure andmaintaining the higher pressure until the pressure no longer drops, andrepeating the inflation to a higher pressure and maintaining until thepressure no longer drops, until the tissue of body lumen yields. Themethod includes keeping the balloon inflated for 1 minute to 7 days, 1minute to 1 day, or 1-10 minutes to release the drug into tissue and toprevent bleeding. The method includes deflating the balloon catheter.The method also includes withdrawing the scope and the balloon catheterassembly from the body lumen.

Various embodiments of the present invention provide a method ofincreasing Q_(max). The method includes inserting a balloon catheterinto a target site in the urinary tract stricture. The balloon catheterincludes an elongated balloon and a coating layer overlying an exteriorsurface of the balloon. The coating layer includes one or morewater-soluble additives and an initial drug load of a therapeutic agent.The method includes inflating the balloon until the coating layercontacts the walls of the urinary tract stricture for an inflationperiod. Feature (a), or (b), or (c), or (a) and (b), or (a) and (c), or(b) and (c), or (a) and (b) and (c), are present: (a) the ratio of theinflated balloon diameter to a normative body lumen diameter at thetarget site is about 1.0 to about 20; or (b) the inflating comprisesinflating the balloon to a pressure equal to or greater than a nominalpressure of the balloon catheter, and the stretch ratio of a nominaldiameter of the balloon catheter to a normative body lumen diameter atthe target site is about 1.0 to about 20; or (c) the inflating comprisesinflating to a pressure greater than the nominal pressure of the ballooncatheter, and the nominal diameter of the balloon catheter is less thanthe inflated balloon diameter; or (d) a combination of (a), (b), and(c). The method includes deflating the balloon after the inflationperiod. The method includes withdrawing the balloon catheter from theurinary tract stricture. The method increases Q_(max), to a minimum of15 mL/s.

Various embodiments of the present invention provide a method ofdecreasing International Prostate Symptom Score (IPSS). The methodincludes inserting a balloon catheter into a target site in the urinarytract stricture. The balloon catheter includes an elongated balloon anda coating layer overlying an exterior surface of the balloon. Thecoating layer includes one or more water-soluble additives and aninitial drug load of a therapeutic agent. The method includes inflatingthe balloon until the coating layer contacts the walls of the urinarytract stricture for an inflation period. Feature (a), or (b), or (c), or(a) and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), arepresent: (a) the ratio of the inflated balloon diameter to a normativebody lumen diameter at the target site is about 1.0 to about 20; or (b)the inflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c). The method includes deflating theballoon after the inflation period. The method includes withdrawing theballoon catheter from the urinary tract. The method decreases the IPSSto 14 or less.

Various embodiments of the present invention provide a method of forminga balloon. The method includes placing a tube including balloon materialinto a balloon mold wherein the balloon mold has a shape including aproximal cone, at least one main body section, at least one neck sectionhaving a diameter less than the at least one main body section, anotherat least one main body section, and a distal cone. The method includespressurizing the interior of the balloon material tube. The method alsoincludes expanding the balloon material tube into contact with theinterior of the mold.

Various embodiments of the present invention provide a method ofsplitting an enlarged prostate or creating a commissurotomy for treatingbenign prostate hyperplasia. The method includes inserting a drug coatedballoon catheter sheath assembly and a scope. The method includesputting the scope and balloon catheter side by side near the externalsphincter. The method optionally includes, prior to, during, or afterthe insertion of the balloon to the target site, flushing the body lumenwith water, saline solution, or a water solution including at least onewater soluble additive. The method includes removing the sheath fromover the balloon and slowly inflating until the pressure drops, theprostatic tissue yields and the commissurotomy is created. The methodincludes increasing the pressure further up to rated burst pressure todilate the prostate more. The method includes keeping the ballooninflated for 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutes torelease the drug into tissue and to prevent bleeding. The methodincludes deflating the balloon catheter and covering the balloon withthe sheath. The method also includes withdrawing the scope and ballooncatheter assembly from the body lumen. Feature (a), or (b), or (c), or(a) and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), arepresent: (a) the ratio of the inflated balloon diameter to a normativebody lumen diameter at the target site is about 1.0 to about 20; or (b)the inflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c).

Various embodiments of the present invention provide a method ofsplitting an enlarged prostate or creating a commissurotomy for treatingbenign prostate hyperplasia. The method includes inserting an uncoatedballoon catheter sheath assembly and a scope. The method includesputting the scope and balloon catheter side by side near the externalsphincter. The method includes removing the sheath from over the balloonand slowly inflating until the pressure drops, the prostatic tissueyields and the commissurotomy is created. The method includes increasingthe pressure further to rated burst pressure to dilate the prostatemore. The method includes keeping the balloon inflated for 1 minute to 7days, 1 minute to 1 day, or 1-10 minutes to prevent bleeding. The methodincludes deflating the uncoated balloon catheter and covering theballoon with the sheath. The method includes withdrawing the scope anduncoated balloon catheter assembly from the body lumen. The methodincludes inserting a drug coated balloon catheter sheath assembly andthe scope. The method includes putting the scope and drug coated ballooncatheter side by side near the external sphincter. The method includesremoving the sheath from over the drug coated balloon and slowlyinflating to rated burst pressure to dilate the prostate more. Themethod includes keeping the balloon inflated for 1 minute to 7 days, 1minute to 1 day, or 1-10 minutes to release the drug into tissue and toprevent bleeding. Feature (a), or (b), or (c), or (a) and (b), or (a)and (c), or (b) and (c), or (a) and (b) and (c), are present: (a) theratio of the inflated balloon diameter to a normative body lumendiameter at the target site is about 1.0 to about 20; or (b) theinflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c).

Various embodiments of the present invention provide a method fortreating benign prostate hyperplasia. The method includes inserting aballoon catheter into a target site in the prostate. The ballooncatheter includes a coating layer overlying an exterior surface of theballoon. The coating layer includes one or more water-soluble additivesand an initial drug load of a therapeutic agent. The method includesinflating the balloon until the coating layer contacts walls of the bodylumen at the target site and the balloon achieves an inflated balloondiameter for an inflation period. Feature (a), or (b), or (c), or (a)and (b), or (a) and (c), or (b) and (c), or (a) and (b) and (c), arepresent: (a) the ratio of the inflated balloon diameter to a normativebody lumen diameter at the target site is about 1.0 to about 20; or (b)the inflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c). The method includes deflating theballoon after the inflation period. The method includes withdrawing theballoon catheter from the body lumen. The method splits the prostaticurethra and prostate, achieves a voiding prostatic urethra diameter ofat least 12 mm, and achieves an inflated diameter of the ballooncatheter of at least 20 mm, or at least 25 mm.

Various embodiments of the present invention provide a method fortreating a urethral stricture. The method includes inserting a ballooncatheter into a target site in the urethra. The balloon catheterincludes a coating layer overlying an exterior surface of the balloon.Wherein the coating layer includes one or more water-soluble additivesand an initial drug load of a therapeutic agent; wherein the therapeuticagent is paclitaxel, docetaxel, taxol, their analogues, rapamycin,sirolimus, everolimus, tacrolimus, MTOR inhibitors, their analogues, andcombinations thereof and the water-soluble additives is at least one ofN-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof. Themethod optionally includes, prior to, during, or after the insertion ofthe balloon to the target site, flushing the body lumen with water,saline solution, or a water solution including at least one watersoluble additive. The method includes inflating the balloon until thecoating layer contacts walls of the body lumen at the target site andthe balloon achieves an inflated balloon diameter for an inflationperiod. Feature (a), or (b), or (c), or (a) and (b), or (a) and (c), or(b) and (c), or (a) and (b) and (c), are present: (a) the ratio of theinflated balloon diameter to a normative body lumen diameter at thetarget site is about 1.0 to about 20; or (b) the inflating comprisesinflating the balloon to a pressure equal to or greater than a nominalpressure of the balloon catheter, and the stretch ratio of a nominaldiameter of the balloon catheter to a normative body lumen diameter atthe target site is about 1.0 to about 20; or (c) the inflating comprisesinflating to a pressure greater than the nominal pressure of the ballooncatheter, and the nominal diameter of the balloon catheter is less thanthe inflated balloon diameter; or (d) a combination of (a), (b), and(c). The method includes deflating the balloon after the inflationperiod. The method includes withdrawing the balloon catheter from thebody lumen. The method achieves a urethra diameter after dilation of atleast 6.7 mm, and the inflated diameter of the balloon catheter is atleast 7 mm.

Various embodiments of the present invention provide a balloon catheterfor treating a urethral stricture. The balloon catheter includes acoating layer overlying an exterior surface of the balloon. The coatinglayer includes one or more water-soluble additives and an initial drugload of a therapeutic agent; wherein the therapeutic agent ispaclitaxel, docetaxel, taxol, their analogues, rapamycin, sirolimus,everolimus, tacrolimus, MTOR inhibitors, their analogues, andcombinations thereof and the water-soluble additives is at least one ofN-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.Feature (a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and(c), or (a) and (b) and (c), are present: (a) the ratio of the inflatedballoon diameter to a normative body lumen diameter at the target siteis about 1.0 to about 20; or (b) the inflating comprises inflating theballoon to a pressure equal to or greater than a nominal pressure of theballoon catheter, and the stretch ratio of a nominal diameter of theballoon catheter to a normative body lumen diameter at the target siteis about 1.0 to about 20; or (c) the inflating comprises inflating to apressure greater than the nominal pressure of the balloon catheter, andthe nominal diameter of the balloon catheter is less than the inflatedballoon diameter; or (d) a combination of (a), (b), and (c). Aftertreatment Q_(max) is at least 15 mL per second and IPSS is no more than14. The urethra diameter after dilation is at least 6.7 mm. The inflateddiameter of the balloon catheter is at least 7 mm.

BRIEF DESCRIPTION OF THE FIGURES

The drawings illustrate generally, by way of example, but not by way oflimitation, various embodiments of the present invention.

FIG. 1A illustrates a balloon catheter having one neck section, inaccordance with various embodiments.

FIG. 1B illustrates a balloon catheter having two neck sections, inaccordance with various embodiments.

FIG. 1C illustrates a balloon catheter having three neck sections, inaccordance with various embodiments.

FIG. 2 illustrates a two-necked drug-coated balloon catheter including acatheter shaft, catheter tip, and Tuohy Borst adapter, in accordancewith various embodiments (the balloon catheter includes a fixed wire,over the wire, and rapid exchanged balloon catheters details not shownin FIG. 2 ).

FIG. 3 is a perspective view of an embodiment of a balloon catheteraccording to the present invention (the balloon catheter includes afixed wire, over the wire, and rapid exchanged balloon catheters detailsnot shown in FIG. 3 ).

FIGS. 4A-4C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 3 , taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of thedisclosed subject matter, examples of which are illustrated in part inthe accompanying drawings. While the disclosed subject matter will bedescribed in conjunction with the enumerated claims, it will beunderstood that the exemplified subject matter is not intended to limitthe claims to the disclosed subject matter.

Throughout this document, values expressed in a range format should beinterpreted in a flexible manner to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges encompassedwithin that range as if each numerical value and sub-range is explicitlyrecited. For example, a range of “about 0.1% to about 5%” or “about 0.1%to 5%” should be interpreted to include not just about 0.1% to about 5%,but also the individual values (e.g., 1%, 2%, 3%, and 4%) and thesub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within theindicated range. The statement “about X to Y” has the same meaning as“about X to about Y,” unless indicated otherwise. Likewise, thestatement “about X, Y, or about Z” has the same meaning as “about X,about Y, or about Z,” unless indicated otherwise.

In this document, the terms “a,” “an,” or “the” are used to include oneor more than one unless the context clearly dictates otherwise. The term“or” is used to refer to a nonexclusive “or” unless otherwise indicated.The statement “at least one of A and B” has the same meaning as “A, B,or A and B.” In addition, it is to be understood that the phraseology orterminology employed herein, and not otherwise defined, is for thepurpose of description only and not of limitation. Any use of sectionheadings is intended to aid reading of the document and is not to beinterpreted as limiting; information that is relevant to a sectionheading may occur within or outside of that particular section.

In the methods described herein, the acts can be carried out in anyorder without departing from the principles of the invention, exceptwhen a temporal or operational sequence is explicitly recited.Furthermore, specified acts can be carried out concurrently unlessexplicit claim language recites that they be carried out separately. Forexample, a claimed act of doing X and a claimed act of doing Y can beconducted simultaneously within a single operation, and the resultingprocess will fall within the literal scope of the claimed process.

The term “about” as used herein can allow for a degree of variability ina value or range, for example, within 10%, within 5%, or within 1% of astated value or of a stated limit of a range and includes the exactstated value or range.

The term “substantially” as used herein refers to a majority of, ormostly, as in at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%,98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or100%.

One aspect of various embodiments of the invention is to deliver atherapeutic agent such as paclitaxel, taxol, docetaxel, rapamycin,sirolimus, tacrolimus, everolimus, mTOR inhibitors, or their analogues,to the wall of a body lumen to treat a narrowing or stricture. Thesedrugs can be considered anti-inflammatory or antiproliferative drugs.The stricture can be in a vascular lumen (e.g., a vascular stenosis in acoronary artery or a peripheral artery) or the stricture can be in anonvascular lumen. The drug can be a water-insoluble drug.

The antimicrobial properties of various fatty acids and monoglyceridesof C8-C12 fatty acids have been investigated for many years. The studieshave confirmed that both fatty acids and monoglycerides can inhibit thegrowth of numerous types of bacteria and viruses. The coatingformulation of the present invention can include various fatty acids andmonoglycerides of C8-C12 fatty acids, such as caprylic acid,monocaprilin, capric acid, monocaprin, lauric acid and monolaurin, asone of the additives for the treatment of various diseases.

Causes of nonvascular body lumen strictures, and related nonvasculardiseases, such as benign prostatic hyperplasia (BPH), urethralstrictures, ureteral strictures, prostate cancer, esophageal strictures,achalasia strictures, strictures in stents, biliary tract strictures,stomach strictures, small intestine strictures, duodenum strictures,jejunum strictures, ileum strictures, colon strictures, rectumstrictures, and large intestine strictures, asthma and chronicobstructive pulmonary disease (COPD), can include cancer, and infectionsand inflammations by pathogens such as bacteria and viruses. Variousembodiments of the present invention provide delivery of coatingformulations to the stricture that contain drugs and additives whichhave properties that kill and inhibit bacteria and viruses.

The present invention provides new methods for treatment of body lumenstrictures to have a long term and persistent effect. The new methodsopen the lumen and prevent, reduce, or minimize renarrowing andrecurrent strictures. The methods involve delivering of therapeuticagents such as anti-inflammatory and antiproliferative drugs (e.g.,paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus,everolimus, mTOR inhibitors, or their analogues) and one or morewater-soluble additives to a target tissue.

Embodiments of the present invention provide a medical device coatingformulation including a drug for treatment of the strictures innonvascular body lumens, and additives that enhance absorption of thedrug into tissue of body lumens. The additives can have antibacterialand antiviral properties. The balloon catheter includes a coating layeroverlying an exterior surface of the balloon, wherein the coating layerincludes one or more water-soluble additives and an initial drug load ofan antiproliferative therapeutic agent.

By coating the exterior surface of the balloon catheter, for example,with a layer including a therapeutic agent and additives, it is usefulin solving problems associated with the coatings. For example, theadditive can have a hydrophilic part and a drug affinity part. The drugaffinity part can be a hydrophobic part and/or can have an affinity tothe therapeutic agent by hydrogen bonding and/or van der Waalsinteractions. Surprisingly, additives according to embodiments of thepresent invention which include a hydrophilic part and a drug affinitypart, in combination with an antiproliferative therapeutic agent, forman effective drug delivery coating on a medical device without the useof oils and lipids, thereby avoiding the lipolysis dependence and otherdisadvantages of conventional oil-based coating formulations. Moreover,the additives according to embodiments of the present inventionfacilitate rapid drug elution and superior permeation of drug intotissues at a disease site. Thus, coatings according to embodiments ofthe present invention provide an enhanced rate and/or extent ofabsorption of the antiproliferative therapeutic agent in nonvasculardiseased tissues or nonvascular body lumens. In embodiments of thepresent invention, the coated device delivers antiproliferativetherapeutic agent to nonvascular tissues during a very brief deploymenttime of less than 10 minutes, less than 2 minutes, and reducesrenarrowing and reoccurring of the strictures of a nonvascular bodylumen.

Various embodiments of the present invention relate to a medical devicefor delivering a therapeutic agent to strictures of vascular ornonvascular body lumen, the device including a layer overlying anexterior surface of the medical device. The device includes one of aballoon catheter, a fixed wire balloon catheter, over the wire ballooncatheter, rapid exchange balloon catheter, a perfusion balloon catheter,a spaced double balloon, a cutting balloon catheter, a scoring ballooncatheter, or an infusion catheter (e.g., a distal perforated druginfusion tube, a perforated balloon, spaced double balloon, porousballoon, or a weeping balloon). The balloon catheter includes anelongated balloon having a narrowed diameter middle section. The ballooncatheter includes at least one neck section on the balloon including asmaller diameter than the main diameter, the at least one neck sectiondividing the balloon into at least two main sections each having adiameter equal to the main diameter or different than the main diameter.Further, the nonvascular lumen or nonvascular stricture includes one ofesophagus, airways, sinus, trachea, colon, biliary tract, stomach, smallintestine, duodenum, jejunum, ileum, rectum, large intestine, urinarytract, prostate, urethra, ureter, and other nonvascular lumens. Vascularlumens include arteries, veins, or any lumens with blood. Nonvascularlumens include those lumens without blood. The balloon catheters shaftsand balloon materials may be constructed of polyether-amide blockcopolymers, polyamides, nylons, or their blends.

In some embodiments, the additive is at least one of a surfactant and achemical compound. A coating layer overlying the exterior of the medicaldevice can include one or more water-soluble additives. A coating layeroverlying the exterior of the medical device can include one or morewater-soluble additives (e.g., a water-soluble first additive, awater-soluble second additive, and a water-soluble third additive).

The medical device can further include a dimethylsulfoxide solventlayer, wherein the dimethylsulfoxide solvent layer is overlying theexterior surface of the medical device.

The device can be capable of releasing the therapeutic agent and theadditive and delivering therapeutic agent to the tissue in about 0.1 to10 minutes. The concentration of the therapeutic agent in the layer canbe from 1 to 20 μg/mm², measured when the balloon is inflated to nominaldiameter. The concentration of the therapeutic agent in the layer can befrom 2 to 10 μg/mm².

In some embodiments, the additives can enhance release of thetherapeutic agent off the balloon. The additive can enhance penetrationand absorption of the therapeutic agent in tissue. The additive can havea water and ethanol solubility of at least 1 mg/ml and the therapeuticagent can be water-insoluble.

The layer overlying the exterior surface of the medical device caninclude a therapeutic agent and at least two additives, wherein each ofthe additives includes a hydrophilic part and a drug affinity part,wherein the drug affinity part is at least one of a hydrophobic part, apart that has an affinity to the therapeutic agent by hydrogen bonding,and a part that has an affinity to the therapeutic agent by van derWaals interactions, and wherein each additive is soluble in polarorganic solvent and is soluble in water. In one aspect of thisembodiment, the polar organic solvent is chosen from methanol, ethanol,isopropanol, acetone, dimethylformide, tetrahydrofuran, methylethylketone, dimethylsulfoxide, acetonitrile, ethyl acetate, and chloroformand mixtures of these polar organic solvents with water. In anotheraspect of this embodiment, the device further includes a top layeroverlying the surface of the layer overlying the exterior surface of themedical device to reduce loss of drug during transit through a body tothe target tissue.

In some embodiments, the additive reduces crystal size and number ofparticles of the therapeutic agent, and wherein the additive iswater-soluble and the therapeutic agent is not water-soluble. Theadditive can have a fatty chain of an acid, ester, ether, or alcohol,wherein the fatty chain can directly insert into lipid membranestructures of the tissue. The additive can penetrate into and rearrangelipid membrane structures of the tissue. The additive can have one ormore functional groups which have affinity to the drug by hydrogenbonding and/or van der Waals interactions. In some embodiments, theadditive can be at least one of a surfactant and a chemical compound,and wherein the chemical compound has a molecular weight of from 50 to750 g/mol. The chemical compound can have more than four hydroxylgroups. In some embodiments, the chemical compound having more than fourhydroxyl groups has a melting point of 120° C. or less, and the chemicalcompound is an alcohol or an ester. In some embodiments, the therapeuticagent is not water soluble.

The medical device coating for delivering a drug to a nonvascular tissueor nonvascular stricture that can be prepared from a mixture. Thecoating can be prepared from a mixture including an organic phasecontaining drug particles dispersed therein and an aqueous phasecontaining a water-soluble additive. The water-soluble additive can bechosen from polyethylene glycol, polyvinyl alcohol,polyvinylpyrrolidinone, polypeptides, water-soluble surfactants,water-soluble vitamins, and proteins. The preparation of the mixture caninclude homogenization under high shear conditions and optionally underpressure.

The coating layer overlying an exterior surface of the medical devicecan consists essentially of the therapeutic agent and the additive. Thecoating layer overlying an exterior surface of the medical device canconsists essentially of a therapeutic agent, a water-soluble firstadditive and a water-soluble second additive. The coating overlying anexterior surface of the medical device can consist essentially of atherapeutic agent, and one or more water-soluble additives (e.g., awater-soluble first additive, a water-soluble second additive, and awater-soluble third additive).

In some embodiments, a method for treating a stricture in a nonvascularbody lumen includes inserting a balloon catheter including a coatinglayer into an body stricture, wherein the stricture is one of urethralstrictures, benign prostatic hyperplasia (BPH) strictures, ureteralstrictures, esophageal strictures, achalasia strictures, biliarystrictures, stomach strictures, small intestine strictures, duodenumstrictures, jejunum strictures, ileum strictures, colon strictures,rectum strictures, strictures in stents, large intestine strictures, andsinus strictures, wherein the coating layer includes a drug and anadditive, inflating the balloon catheter and releasing the drug to awall of the stricture, deflating the balloon; and withdrawing theballoon catheter, wherein the residual drug can be about 1 to 70% of thetotal loading drug on the balloon catheter. In one aspect of thisembodiment, the additive enhances absorption of the drug into tissue ofthe nonvascular body lumen.

Some drugs for use in various embodiments that are consideredparticularly suitable for the airway, sinus and other nasal lumens arecorticosteroids such as, budesonide, flunisolide, triamcinolone,beclomethasone, fluticasone, mometasone, mometasone furoate,dexamethasone, hydrocortisone, methylprednisolone, prednisone, cotisone,betamethasone, triamcinolone acetonide, or the like.

Various embodiments relate to a method for treating a stricture in anonvascular body lumen and can include flushing the lumen with water,saline solution, or water solutions of the additives described herein,inserting a balloon catheter including a coating layer into a bodylumen, wherein the coating layer includes a drug and an additive,inflating the balloon catheter and releasing the drug to a wall of thebody lumen, deflating the balloon, and withdrawing the balloon catheter.A method for treating a stricture in a nonvascular body lumen caninclude infusing water, saline solution, or a water solution includingat least one of the additives described herein, inserting a ballooncatheter including a coating layer into a stricture in a nonvascularbody lumen, wherein the stricture in the nonvascular body lumen is oneof, urethral strictures, ureteral strictures, esophageal strictures,achalasia strictures, strictures in stents, sinus strictures, stomachstrictures, small intestine strictures, duodenum strictures, jejunumstrictures, ileum strictures, rectum strictures, and large intestinestrictures, and biliary tract strictures, wherein the coating layerincludes a drug and an additive, inflating the balloon catheter andreleasing the drug to a wall of the stricture in a nonvascular bodylumen, deflating the balloon, and withdrawing the balloon catheter. Inone aspect of this embodiment, the additive enhances absorption of thedrug into tissue of the nonvascular body lumens. In another aspect ofthis embodiment, the additive includes a hydrophilic part and a drugaffinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions. In another aspect of thisembodiment, the drug is chosen from paclitaxel, docetaxel, taxol andanalogues thereof and rapamycin, sirolimus, everolimus, tacrolimus andanalogues thereof. In another aspect of this embodiment, the additive ischosen from PEG-fatty acids and PEG-fatty acid mono and diesters,polyethylene glycol glycerol fatty acid esters, alcohol-oiltransesterification products, polyglyceryl fatty acids, propylene glycolfatty acid esters, sterol and derivatives thereof, polyethylene glycolsorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugars andderivatives thereof, polyethylene glycol alkyl phenols,polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acidesters, fat-soluble vitamins and salts thereof, water-soluble vitaminsand amphiphilic derivatives thereof, amino acid and salts thereof,oligopeptides, peptides and proteins, and organic acids and esters andanhydrides thereof. In yet another aspect of this embodiment, the drugcan be released to the wall of the airway prior to, during, or after anasthma attack. In yet another aspect of this embodiment, the drug can bereleased to the wall of the esophagus. In yet another aspect of thisembodiment, the drug can be released to the wall of the sinus. In yetanother aspect of this embodiment, the drug can be released to the wallof the biliary tract. In yet another aspect of this embodiment, the drugcan be released to the wall of the urinary tract, prostate, urethral,and ureteral lumens. In yet another aspect of this embodiment, the drugcan be released to the wall of the stomach, small intestine, duodenum,jejunum, ileum, colon, rectum, or large intestine. In another embodimentof this embodiment, the drug can be released to the wall of thenonvascular stricture in the stent.

In various embodiments, the present invention provides a method fortreating a body lumen including inserting a balloon catheter, such asany balloon catheter described herein, to a target site in a body lumen.The method includes inserting the balloon catheter of FIG. 1A, 1B, 1C, 2, or 3 to a target site in the body lumen. The method may includeinserting the balloon catheter and a scope to a target site in the bodylumen side by side or with the balloon catheter in the lumen of thescope. The scope can be an endoscope, enteroscope, colonoscope,sigmoidoscope, rectoscope, anoscope, rhinoscope, bronchoscope, or acystoscope. The scope may be used to ensure that the balloon catheter isproperly positioned within the targeted lumen. The method can include,prior to, during, or after the insertion of the balloon to the targetsite, flushing the body lumen with water, saline solution, or a watersolution including at least one water soluble additive. The methodincludes inflating the balloon until the coating layer contacts walls ofthe stricture in the body lumen at the target site and the balloonachieves an inflated balloon diameter for an inflation period. Feature(a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or(a) and (b) and (c), are present: (a) the ratio of the inflated balloondiameter to a normative body lumen diameter at the target site is about1.0 to about 20; or (b) the inflating comprises inflating the balloon toa pressure equal to or greater than a nominal pressure of the ballooncatheter, and the stretch ratio of a nominal diameter of the ballooncatheter to a normative body lumen diameter at the target site is about1.0 to about 20; or (c) the inflating comprises inflating to a pressuregreater than the nominal pressure of the balloon catheter, and thenominal diameter of the balloon catheter is less than the inflatedballoon diameter; or (d) a combination of (a), (b), and (c). The methodincludes deflating the balloon after the inflation period. The methodalso includes withdrawing the balloon catheter from the stricture in thebody lumen.

In some embodiments, the balloon is inflated until the coating layercontacts walls of the stricture and the stricture is dilated, withsimultaneous transfer of the drug to the stricture. In some embodiments,the balloon is inflated until the coating layer contacts walls of thestricture, the inflation dilates the stricture to increase its diameter,such that the contacting with the stricture can provide fullcircumferential transfer of the drug to the wall of the stricture. Insome embodiments, the portion of the balloon that includes the drug(e.g., in embodiments including less than 100% of the surface areacoated with the drug) can contact the stricture uniformly. In otherembodiments, the contacting of various portions of the surface of theballoon with the stricture is non-uniform.

The inflated diameter of the balloon can be any suitable diameter thatis achieved during or throughout the inflation period such that adesired ratio of the inflated balloon diameter to the normative diameterof the body lumen is achieved. The inflated diameter of the balloon cancorrespond to the pressure used to inflate the balloon during theinflation period. The inflation pressure can be in the range of nominalinflation pressure to rated burst pressure. The nominal pressure is thepressure at the nominal diameter of the inflated balloon catheter. Thenominal diameter is the diameter at the nominal pressure of the ballooncatheter and is specified on the product labeling. In some embodiments,the inflated pressure can be the nominal pressure for the balloon, andthe inflated diameter of the balloon can be about equal to the nominaldiameter of the balloon, or can be less than the nominal diameter of theballoon due to constraint from the stricture. In some embodiments, theinflated pressure of the balloon during the inflation period can beabove or below the nominal pressure and the inflated diameter of theballoon can be, correspondingly, above or below the nominal diameter ofthe balloon.

In various embodiments, the present invention provides a method fortreating a body lumen. The method includes 1) backloading a ballooncatheter into the scope (e.g., cystoscope). The method includes 2)inserting the scope-balloon catheter assembly into the body lumen. Themethod includes 3) inflating the balloon to the initial pressure (forexample 0.5 atm, 1 atm or 1.5 atm) and maintaining the initial pressureuntil the pressure no longer drops, for 1-2 minutes. The method includes4) inflating to the next higher pressure with an 0.5, 1, or 1.5 atmincrease from the previous pressure and maintaining the higher pressureuntil the pressure no longer drops, for 1-2 minutes. The method includes5) repeating the steps of 4) until the lumen tissue, such as prostatictissue, yields. The method includes 6) keeping the balloon inflated for1 minute to 7 days, or 1 minute to 1 day, or 1-10 minutes to release thedrug into tissue and to prevent bleeding. The method includes 7)deflating the balloon catheter. The method includes 8) withdrawing thescope-balloon catheter assembly from the body lumen. In this embodiment,the scope may be used to ensure that the balloon catheter is properlypositioned before and/or during the inflation.

In various embodiments, the present invention provides a method fortreating a body lumen. The method includes 1) inserting a flexible scopeand a balloon catheter in a sheath to the body lumen side by side. Themethod includes 2) removing the sheath from over the balloon andinflating to the initial pressure (for example 0.5 atm, 1 atm or 1.5atm) and maintaining the initial pressure until the pressure no longerdrops, for 1-2 minutes. The method includes 3) inflating to the nexthigher pressure with an 0.5, 1, or 1.5 atm increase from the previouspressure and maintaining the higher pressure until the pressure nolonger drops, for 1-2 minutes. The method includes 4) repeating thesteps of 3) until the tissue of body lumen yields. The method includes5) keeping the balloon inflated for 1 minute to 7 days, 1 minute to 1day, or 1-10 minutes to release the drug into tissue and to preventbleeding. The method includes 6) deflating the balloon catheter. Themethod includes 7) pulling balloon catheter back inside of the sheath.The method includes 8) withdrawing the scope and the ballooncatheter/sheath from the body lumen. In this embodiment, the scope maybe used to ensure that the balloon is properly positioned before and/orduring inflation.

In various embodiments, the present invention provides a method fortreating a body lumen. The method includes 1) inserting a flexible scopeto the body lumen. The method also includes 2) inserting a ballooncatheter and the scope in the body lumen side by side. The methodincludes 3) inflating to the initial pressure (for example 0.5 atm, 1atm or 1.5 atm) and maintaining the initial pressure until the pressureno longer drops, for 1-2 minutes. The method includes 4) inflating tothe next higher pressure with 0.5, 1, or 1.5 atm increasing from theprevious pressure and maintaining the higher pressure until the pressureno longer drops for 1-2 minutes. The method includes 5) repeating thesteps of 4) until the tissue of body lumen yields. The method includes6) keeping the balloon inflated for 1 minute to 7 days, 1 minute to 1day, or 1-10 minutes to release the drug into tissue and to preventbleeding. The method includes 7) deflating the balloon catheter. Themethod includes 8) withdrawing the scope and the balloon catheterassembly from the body lumen. In this embodiment, the scope may be usedto ensure that the balloon catheter is properly positioned before and/orduring inflation.

In various embodiments, the present invention provides a method fortreatment of benign prostate hyperplasia. The method includes 1)inserting a balloon catheter sheath assembly and the scope (e.g.,cystoscope). The method includes 2) putting the scope and ballooncatheter side by side near the external sphincter. The method includes3) removing the sheath from over the balloon and inflating to theinitial pressure (for example 0.5 atm, 1 atm or 1.5 atm) and maintainingthe initial pressure until the pressure no longer drops for 1-2 minutes.The method includes 4) inflating to the next higher pressure with an0.5, 1, or 1.5 atm increase from the previous pressure and maintainingthe higher pressure until the pressure no longer drops, for 1-2 minutes.The method includes 5) repeating the steps of 4) until the prostatictissue yield and the commissurotomy is formed. The method includes 6)keeping the balloon inflated for 1 minute to 7 days, 1 minute to 1 day,or 1-10 minutes to release the drug into tissue and to prevent bleeding.The method includes 7) deflating the balloon catheter. The methodincludes 8) withdrawing the scope and balloon catheter assembly from thebody lumen. Feature (a), or (b), or (c), or (a) and (b), or (a) and (c),or (b) and (c), or (a) and (b) and (c), are present: (a) the ratio ofthe inflated balloon diameter to a normative body lumen diameter at thetarget site is about 1.0 to about 20; or (b) the inflating comprisesinflating the balloon to a pressure equal to or greater than a nominalpressure of the balloon catheter, and the stretch ratio of a nominaldiameter of the balloon catheter to a normative body lumen diameter atthe target site is about 1.0 to about 20; or (c) the inflating comprisesinflating to a pressure greater than the nominal pressure of the ballooncatheter, and the nominal diameter of the balloon catheter is less thanthe inflated balloon diameter; or (d) a combination of (a), (b), and(c).

Various embodiments of the present disclosure are directed to thetreatment of strictures in body lumens by delivering of an effectiveamount of a therapeutic agent such as anti-inflammatory andantiproliferative drugs (e.g., rapamycin, sirolimus, everolimus,tacrolimus, paclitaxel, taxol, docetaxel or their analogues) to a targettissue. The strictures in body lumens include vascular strictures,nonvascular strictures, urethral strictures, ureteral strictures,esophageal strictures, achalasia strictures, strictures in stents, sinusstrictures, biliary tract strictures, stomach strictures, smallintestine strictures, duodenum strictures, jejunum strictures, ileumstrictures, colon strictures, rectum strictures, and large intestinestrictures. Embodiments of the present disclosure are directed tomethods for treating at least one of stenosis of vascular andnonvascular lumens, benign prostatic hyperplasia (BPH), narrowingurethral, prostate cancer, asthma, and chronic obstructive pulmonarydisease (COPD). The treatment is intended for a variety of animals, suchas premature neonates to adult humans.

The drug on the coating of the balloon catheter can be released to thetargeted body lumen. The multiple-sectioned balloon with the necksection having a smaller diameter mechanically anchors the balloon inthe body lumen, therefore it prevents slipping of the balloon in thebody lumen. If the balloon slips or moves off the targeted diseasedsite, the target site may be missed, and the healthy lumen may beinjured.

In various embodiments, the present invention has advantages, at leastsome of which are unexpected. For example, coating the exterior surfaceof a balloon catheter with a layer including a therapeutic agent andadditives that have a hydrophilic part and a drug affinity part isuseful for treating the disorders disclosed herein. The drug affinitypart is a hydrophobic part and/or has an affinity to the therapeuticagent by hydrogen bonding and/or van der Waals interactions.Surprisingly, additives according to embodiments of the presentinvention, which include a hydrophilic part and a drug affinity part, incombination with a therapeutic agent, forms an effective drug deliverycoating on a medical device. Moreover, the additives according toembodiments of the present invention can facilitate rapid drug elutionand superior permeation of drug into tissues at a disease site. Thus,coatings according to embodiments of the present invention can providean enhanced rate and/or extent of absorption of the therapeutic agent indiseased tissues or body lumens. In embodiments of the presentinvention, the coated device can deliver therapeutic agent to tissuesduring a very brief deployment time of less than 10 minutes (e.g., lessthan 2 minutes), and can reduce renarrowing and reoccurring of thestrictures of a body lumen, such as compared to other balloon catheterslacking such a neck section or configuration of neck sections.

In various embodiments, the balloon catheter of the present invention iscompatible with flexible or rigid scopes that allow visualization of thetreatment zone, allowing more accurate and more efficient placement thanother balloon catheters. The scope can be an endoscope, enteroscope,colonoscope, sigmoidoscope, rectoscope, anoscope, rhinoscope,bronchoscope, or a cystoscope. In various embodiments, the ballooncatheter of the present invention is self-seeking, in that the necksection of the balloon catheter directs the balloon catheter to a properposition during inflation (e.g., with the neck section of the ballooncatheter, such as a distal-most neck section, in the bladder neck) evenif the balloon catheter is slightly off-position at the time ofinitiation of inflation.

Balloon Catheter and Method of Using the Same.

In various embodiments, the present invention provides a ballooncatheter for delivering a therapeutic agent to a target site of a bodylumen. The balloon catheter may include an elongated balloon havingmultiple main, or body, sections and at least one neck section with asmaller diameter than that of the main sections. The balloon cathetercan include an elongated balloon having a main diameter, such asmultiple main sections having the main diameter or having an averagediameter equal to the main diameter. The multiple-sectioned balloon withsmaller a diameter neck section mechanically anchors the balloon in thebody lumen; therefore, it can prevent slipping of the balloon in thebody lumen. If the balloon slips away from the targeted diseased site itmay be missed and the site of health lumen may be injured. The ballooncatheter can include at least one neck section on the balloon includinga smaller diameter than the main diameter. The balloon catheter can alsoinclude a coating layer overlying an exterior surface of the balloon.The coating layer can include one or more water-soluble additives and aninitial drug load of a therapeutic agent (e.g., paclitaxel, taxol,docetaxel, their analogues, rapamycin, sirolimus, everolimus,tacrolimus, their analogues, and combinations thereof). In a method ofusing the balloon catheter, Feature (a), or (b), or (c), or (a) and (b),or (a) and (c), or (b) and (c), or (a) and (b) and (c), are present: (a)the ratio of the inflated balloon diameter to a normative body lumendiameter at the target site is about 1.0 to about 20; or (b) theinflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c).

The main diameter of the balloon can be the diameter of the mainsections of the balloon when the balloon is inflated. In someembodiments, the inflated pressure used to determine the main diametercan be any pressure that eliminates any folded or creased areas of theballoon and achieves taughtness of the balloon. The inflated pressureused to determine the main diameter can be a pressure such that theinflated balloon has a shape and size that corresponds to the desiredshape and size of the balloon during the intended treatment of the bodylumen. The inflated pressure used to determine the main diameter can bethe nominal pressure of the balloon, such that the nominal diameter ofthe balloon catheter is equal to the main diameter of the balloon.

In one embodiment, the drug coated balloon includes two main sections atboth ends with the same diameters, one neck section with a smallerdiameter between the two main sections, and the two cones at proximaland distal balloon body. The drug coated balloon can include three mainsections with the same diameters, two neck sections with a smallerdiameter, wherein three main sections and two neck sections are alignedalternatively and the neck sections are adjacent to the main sectionswith larger diameters, and the two cones at proximal and distal balloonbody. The drug coated balloon can include four main sections with alarger diameter, three neck sections with a smaller diameter, whereinthe four main sections with a larger diameter and three neck sectionsare aligned alternatively and the neck sections are adjacent to the mainsections with larger diameters, and the two cones at proximal and distalballoon body. The drug coated balloon can include five main sectionswith a larger diameter, four neck sections with a smaller diameter,wherein the five main sections with a larger diameter and four necksections are aligned alternatively and the neck sections are adjacent tothe main sections with larger diameters, and the two cones at proximaland distal balloon body. The balloon catheter includes at least one necksection on the balloon including a smaller diameter than the balloondiameter of the main sections. The balloon catheter can include anelongated (e.g., cylindrical) balloon having multiple sections withvarious diameters. Feature (a), or (b), or (c), or (a) and (b), or (a)and (c), or (b) and (c), or (a) and (b) and (c), are present: (a) theratio of the inflated balloon diameter to a normative body lumendiameter at the target site is about 1.0 to about 20; or (b) theinflating comprises inflating the balloon to a pressure equal to orgreater than a nominal pressure of the balloon catheter, and the stretchratio of a nominal diameter of the balloon catheter to a normative bodylumen diameter at the target site is about 1.0 to about 20; or (c) theinflating comprises inflating to a pressure greater than the nominalpressure of the balloon catheter, and the nominal diameter of theballoon catheter is less than the inflated balloon diameter; or (d) acombination of (a), (b), and (c). The multiple sectioned balloon withsmaller necks increases the friction between the balloon and the bodylumen; therefore, it prevents the slipping of the balloon in the bodylumen.

The drug-coated balloon catheter can be a medical device for thetreatment of benign prostatic hyperplasia (BPH). The balloon cathetercan dilate the prostatic urethra and can include a catheter shaft forinsertion into the urethra and a compliant, semi-compliant, ornon-compliant balloon for inflation in the prostatic urethra. Theballoon can be coated with a therapeutic agent which is delivered to theprostate tissue and prostatic urethra upon balloon inflation. Theballoon can be positioned within the prostate using any suitable method,such as via a separate location balloon in the bladder, a locationballoon in the bulbous urethra, or the catheter shaft can be scope-(e.g., cystoscope-) compatible allowing placement via directvisualization, or the catheter may be side by side with the scope. Forexample, several possible catheter designs allow direct visualization ofthe balloon during positioning and inflation. One design iscystoscope-compatible, with the catheter being back-loaded through theworking channel. Once through the cystoscope, a Touhy Borst adapter and1-way stopcock can be attached to the catheter shaft to allow inflationof the balloon. Another design can include a multilumen catheter with alumen in the center of the shaft that allows the optics of a rigidcystoscope to be inserted and positioned next to the proximal edge ofthe balloon.

In some embodiments, when treating the prostate, the balloon cathetershould be sized so that the main body section(s) of the catheter arebetween the bladder neck sphincter (at the outlet of the bladder) andthe external sphincter. In other embodiments, the main body section(s)of the catheter are above the external sphincter, placed through theprostate and one or more body sections go through the bladder necksphincter and sit in the bladder. In these embodiments, preferably, theneck region of the balloon catheter is aligned with the bladder neck. Asdiscussed herein, a scope equipped with visualization can be used toproperly size and place the balloon catheter. In embodiments where theballoon catheter includes a soft tip, a Coude tip, or the like, the tipmay be inserted into the internal urethral sphincter (e.g., the bladderneck sphincter) to aid in placing the balloon catheter in the desiredlocation.

The balloon catheter can alleviate the lower urinary tract symptoms(LUTS) due to BPH through the direct dilation of the prostatic tissue.Dilation of the prostate with the balloon with ratio of inflated balloondiameter of normative body lumen diameter at the target site of 1.0 to20, or with a balloon having a stretch ratio of the nominal balloondiameter to the normative body lumen diameter at the target site of 1.0to 20, can create a commissurotomy at the natural plane that separatesthe lateral sections in the transition zone of the prostate.Concurrently, drug can be released from the coating into the prostatictissue, which can, for example, preventing enlargement of the prostateand renarrowing of the newly formed opening.

In various embodiments, during inflation of the balloon in a body lumen(e.g., during performance of a method of the present invention), thenominal balloon diameter of the catheter (e.g., the diameter normallyachieved at nominal pressure) can be such that the ratio of the nominalballoon diameter to the normative diameter of the body lumen at thelocation of treatment is any suitable ratio, such as about 1.01 to about20, or about 1.01 to about 15, or about 1.2 to about 10, or about 1.31to about 8, or less than, equal to, or greater than about 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more. In some embodiments, the inflated diameter of the balloon atthe target site during inflation to the nominal pressure is equal to thenominal diameter; however, during actual use, some strictures mayprevent achievement of the nominal diameter, or can constrain theinflated balloon to form “dog-bone” shape. The nominal balloon diameterat predetermined pressure (e.g., 2 atm, 3 atm, 6 atm, or 9 atm) can bedifferent for different diameters of balloons for various diseases. Forexample, nominal diameters of urethral stricture balloons can be 6 mm, 8mm, 10 mm, 12 mm, and 14 mm for 6 mm, 8 mm, 10 mm, 12 mm, and 14 mmballoon catheters at 6 atm inflation. The nominal diameters of the BPHstricture balloons can be 25 mm, 30 mm, 35 mm, 40 mm, and 45 mm withballoon lengths of 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55mm, and 60 mm balloon catheters at nominal pressure of 2 atm, 3 atm, 4atm, 6 atm, or 9 atm inflation. Table 1 illustrates examples of nominalballoon sizes, nominal pressures, and ratios of minimal balloon diameterto normative lumen diameter for used to treat strictures of variousdiseases. Nominal pressure is the pressure required to bring the balloonto its labeled nominal diameter in an unconstrained pressure ramp test.Nominal diameter is the desired diameter that the product is labeledwith. All physicians purchase balloons and select balloons for useaccording to the nominal diameter. The rated burst pressure is themaximum pressure that the balloon can be inflated to and have a veryhigh confidence that it will not burst, a labeling requirement forballoon catheters that is calculated from a statistical analysis of thepressures observed when the balloons burst in an unconstrained pressureramp test.

TABLE 1 Examples of nominal balloon sizes, nominal pressures, and ratiosof minimal balloon diameter to normative lumen diameter for used totreat strictures of various diseases. Nominal Ratio of nominal balloonRated balloon diameter × Nominal burst diameter/ length pressurepressure normative Disease (mm) (atm) (atm) lumen diameter BPH 20-50 ×1.5 2 2.5-10 20-80, minimum, minimum, such as such as 2 such as 4 30-40× atm or or more 35-45 more Urethral 6-14 × 3 8 1-2 stricture 20-180,minimum, minimum, such as such as 8 such as 10- 6-14 × or more 12 30-50Esophageal 6-20 × 3 9 1-2 stricture 30-80 minimum minimum Achalasia30-40 × 1.5 9 1-2 (stricture of 80-100 minimum minimum lower esophagus)Gastrointestinal 6-20 × 3 9 1-2 strictures 40-60 minimum minimum Biliary4-10 × 3 9 1-2 strictures 20-40 minimum minimum

In various embodiments, the balloon catheter can be sufficient such thatat a predetermined pressure (e.g., the nominal pressure) the balloon canhave any suitable ratio of inflated balloon catheter diameter to anormative diameter of the body lumen at the location of treatment; forexample, at a pressure of about 1 atm (304 kPa) to about 30 atm (3040kPa) (e.g., about 1 atm or less, or less than, equal to, or more thanabout 4 atm, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,22, 24, 26, 28, or about 30 atm or more).

The stretch ratio is defined herein, unless otherwise indicated, as theratio of the nominal diameter of the balloon to the normative diameterof the body lumen in the area being treated by the balloon catheter. Thenominal diameter of the balloon is the diameter the balloon achieves inan unrestricted environment at the nominal pressure. The normative lumendiameter is the average of the diameters of healthy lumen adjacent tothe stricture, stenosis, or lesion, that is proximal and distal of thestricture or stenosis or lesion of the lumen. For the urinary tract, forexample, in the urethra and prostatic urethra, the normative body lumendiameter will be the average diameter of the voiding urethra of thehealthy lumen distal and proximal to the obstruction. For all lumens, ifthe average diameter of healthy tissue distal and proximal is notobtainable, the normative body lumen diameter will be the diameter ofwhat the lumen would have been with biological matter flowing through ithad it been healthy. The inflated balloon diameter can be the actualdiameter of the balloon following inflation, which in some embodimentscan equal to, less than, or greater than the nominal diameter of theballoon. In various embodiments, the stretch ratio of the ballooncatheter of the present invention makes it more effective for treatingnon-vascular lumens than other catheters. During performance of a methodof the present invention, the stretch ratio of can be selected to be anysuitable ratio that achieves the desired ratio of actual inflatedballoon diameter to normative lumen diameter at the range of pressuresused during the method. In various embodiments, the stretch ratio of theballoon can be about 1.01 to about 20, 1.31 to 20, or about 1.01 toabout 15, or about 1.1 to about 10, 1.2 to 10, 1.3 to 10, 1.31 to 10,1.4 to 10, 1.5 to 10, 1.6 to 10, 1.7 to 10, 1.8 to 10, 2 to 10, 2.2 to10, 2.5 to 10, or less than, equal to, or greater than about 1.1, 1.2,1.3, 1.31, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 4, 5, 6, 7, 8, 9,10, 12, 14, 16, 18, or about 20 or more; such a stretch ratio can resultin a desired ratio of inflated balloon diameter to normative lumendiameter at the pressures used during the inflation period that can bethe same, similar to, or different than the stretch ratio, such as about1.01 to about 20, 1.31 to 20, or about 1.01 to about 15, or about 1.1 toabout 10, 1.2 to 10, 1.3 to 10, 1.31 to 10, 1.4 to 10, 1.5 to 10, 1.6 to10, 1.7 to 10, 1.8 to 10, 2 to 10, 2.2 to 10, 2.5 to 10, or less than,equal to, or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.7,1.8, 1.9, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20or more.

In various embodiments, the method includes measuring the body lumenstricture to be treated. The distal and proximal healthy tissue diameterand the length of the stricture can be assessed to select the drugcoated balloon to be used. The physician will select a balloon based onthe normative diameter of the body lumen stricture and achieving astretch ratio of the nominal diameter of the balloon to the normativediameter of the body lumen stricture of 1.0-20, or 1.1-15, or 1.2-10, or1.31-8. The physician can then inflate the balloon to at least thenominal pressure, and in some cases, can inflate the balloon past thenominal pressure, up to the rated burst pressure of the balloon. Therange of pressure used during the inflation period can be called theworking pressure range of the drug coated balloon. In some cases, themethod can include exceeding the rated burst pressure of the balloon.Because the nominal diameter of the balloon is determined without anyconstrictions, the inflated diameter of the balloon during treatmentwhile in the stricture will be about the same or less or greater thanthe nominal diameter. At or above burst pressure, the inflated diameterof the balloon can be less than the nominal diameter, equal to thenominal diameter, or can exceed the nominal diameter. For example, abody lumen stricture can be measured to have a normative diameter of 10mm. The physician can choose a 14 mm nominal diameter drug coatedballoon that has a nominal pressure of 6 atm and a rated burst pressureof 10 atm. The stretch ratio is 1.4. The physician would inflate theballoon to at least 6 atm and in some cases inflate to 10 atm and insome cases inflate to over 10 atm to achieve the desired inflatedballoon diameter during treatment.

In various embodiments, the balloon catheter has one or more necksections separating one or more main sections, and the at least one necksection of the balloon catheter of the present invention, or theconfiguration of the one or more neck sections, allows the ballooncatheter to stay in place during treatment more consistently andeffectively to dilate the stricture and deliver the drug, as compared toother balloon catheters lacking such a neck section or configuration ofneck sections.

In various embodiments, the balloon catheter can be assembled with asheath. The catheter assembly and scope (e.g., cystoscope) are insertedtransurethrally into the prostatic urethra and they are positioned sideby side near the external sphincter. Using the live video feed from thescope, the external sphincter can be located. The balloon can bepositioned adjacent to the external sphincter and within the prostaticurethra. The balloon dilation, drug release, and balloon deflation canbe visualized by the scope.

In various embodiments, the balloon catheter can be assembled with acystoscope by backloading the shaft through the working channel andattaching a Tuohy Borst and one-way stopcock at the proximal end. Thecystoscope-catheter assembly is inserted transurethrally into theprostatic urethra. Using the live video feed from the cystoscope, theexternal sphincter can be located. The balloon can be positionedadjacent to the external sphincter and within the prostatic urethra.

In some embodiments, when treating the prostate, it is preferable toplace the proximal balloon waist in the external sphincter so that theexternal sphincter is not dilated. It is also preferable to size theballoon so that when the balloon waist is in the external sphincter, aballoon neck (e.g., a distal-most balloon neck) is aligned with thebladder neck. This arrangement provides holding forces so that theballoon will not slip during expansion. If a balloon neck cannot bealigned with the bladder neck, it may be preferable to inflate theballoon slowly so that the prostate can yield as the balloon isinflated.

Once properly positioned the balloon is dilated, such as using aninflation device with a pressure gauge. The balloon can be inflatedslowly, allowing the prostatic tissue to yield and reducing thepropensity for the balloon to slip proximally into the bladder and slipbackward distally. Although a single- or multi-necked shape of theballoon can prevent balloon movement by aligning the distal-most neckwith the bladder neck, in some abnormal situations such as with anenlarged median lobe (e.g., about 10-15% of cases) the neck of theballoon may not stay aligned to the neck of the bladder during inflationand additional techniques can be useful to further prevent balloonmigration. In some examples, inflating at a rate of about 0.5 to 1atm/min can prevent balloon movement. As the tissue yields, the balloonpressure correspondingly drops, allowing for additional fluid to beinstilled within the balloon without increasing the pressure. When thepressure is stable for about 1-2 minutes the pressure can be increasedin 0.5 or 1 atm increments and maintained in a similar method. Thepressure can be continually increased, following this method ofincreasing pressure, allowing pressure to stabilize after pressuredrops, and continuing to increase pressure, until a commissurotomy or asplit is achieved. Alternatively, a very slow inflation can preventballoon migration to achieve a commissurotomy or a prostate split. Oncea commissurotomy or a prostatic urethra and prostate split is observedand confirmed with the video feed from the scope, mechanicaldecompression can be achieved. The balloon can remain inflated for aperiod of about 1 minute to 7 days, 1 minute to 1 day, or 1-10 minutesto allow the drug in the coating to transfer into the tissue. Once thetreatment is completed, the balloon can be deflated and the catheter andscope can be removed from the body lumen of the patient.

In some embodiments, when treating the prostate, it may be desirable topredilate the stricture. In this embodiment, the predilation cathetermay be shorter and/or of less diameter than the drug-coated balloontreatment catheter. In this scenario, the predilation catheter ispositioned with the proximal waist of the balloon in the externalsphincter and a neck region aligned with the bladder neck. The balloonis slowly inflated as described herein to aid in yielding the prostatewhile protecting against balloon slippage. Once inflated, thepredilation balloon is deflated and removed and the drug-coatedtreatment balloon is inserted. The treatment balloon's proximal waist isaligned with the external sphincter. If the BPH was properly predilated,it is not as necessary to align a balloon neck with the bladder neck asthe balloon will not be as prone to slipping as it would be in anon-predilated body lumen.

The drug-coated balloon catheter can include an elongated balloon bodywith multiple main sections, two cones at distal and proximal ends ofthe balloon body, an inflation lumen, and a wire lumen, wherein theballoon body includes at least two main sections with a larger diameterand at least one neck section with a smaller diameter, wherein the mainsection with a larger diameter and neck section are alignedalternatively and adjacently. The elongated balloon can have a generallycylindrical shape, with the exception of any neck section on theballoon, any tapered sections (e.g., cones) between the neck section andthe main sections having the main diameter, and any tapered or shapedsections at the longitudinal ends of the balloon. The elongated ballooncan have any suitable profile taken perpendicular to a longitudinaldirection of the balloon, such as circular (e.g., cylindrical balloon),oval, or polygonal (e.g., pentagonal, hexagonal, heptagonal, octagonal,and the like), or a combination thereof. The diameter of anon-cylindrical balloon can be the largest size perpendicular to thelongitudinal direction.

The balloon can be formed from any suitable material, such as anon-compliant or semi-compliant biocompatible material. In someembodiments, the balloon can be made by blow-forming to accomplish adesired geometry. In some embodiments, the balloon can include materialsthat do not interact with the drug coating, or materials such as nylon(e.g., any suitable nylon, such as nylon 6,6 or nylon 12), polyetherblock amide (PEBA), polyethylene terephthalate (PET), polyvinylchloride(PVC), polyester, polyurethane, derivatives thereof, or combinationsthereof.

The balloon can have any suitable size. The balloon can be designed tofit within the prostatic urethra with the distal section of the balloonbeing positioned in the bladder. Main diameters and nominal balloondiameters can range from about 5 mm to about 50 mm, 25 mm up to 45 mm,at least 10 mm, at least 15 mm, at least 20 mm, at least 30 mm, such asabout 5 mm or less, or less than, equal to, or greater than about 6 mm,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 32, 34, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, or about 50 mm or more; main section diameters can independentlyrange from any of these ranges or specific sizes. The balloon can have alength of about 20 mm to about 160 mm, 40 mm to about 80 mm, or about 20mm or less, or less than, equal to, or greater than about 22 mm, 24, 26,28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62,64, 66, 68, 70, 72, 74, 76, 78 mm, or about 80 mm or more. Balloonlength and diameter can be selected based on the unique prostate anatomyof the patient.

The balloon can include at least one neck section. The neck section is asection of the balloon having a smaller diameter than the main nominaldiameter of the balloon. The neck section diameter can be about 5 mm toabout 35 mm, 10 mm to about 35 mm, or about 5 mm or less, or less than,equal to, or greater than about 6 mm, 8, 10, 12, 14, 16, 18, 20, 22, 24,26, 28, 30, 32, 34 mm, or about 35 mm or more. The at least one necksection can have a diameter that is independently about 5% to about 99%of the main diameter, such as about 20% to about 99%, or about 5% orless, or less than, equal to, or greater than about 10%, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or about99% or more. In some embodiments, the neck section diameter is from 35%to 75% of the diameter of the main section of the balloon. In someembodiments where the balloon main section has a nominal diameter of 35to 40 mm, the neck section would have a diameter of 15 to 20 mm. In someembodiments, if the neck diameter is too similar to the diameter of themain section, its ability to prevent balloon slippage may be lessened.

The neck section can be a rigid or semi-rigid neck section, such thatthe diameter of the neck section (e.g., the portion of the neck sectionhaving the neck section diameter) remains substantially static duringinflation of the balloon. The neck section can include a substantiallynonelastic (e.g., non-compliant, or minimally non-compliant) portion ofthe balloon, a reinforced portion of the balloon, or a combinationthereof. The neck section can include an inelastic material circulatedaround a circumference of the neck section, such as a suture ormonofilament or multifilaments of such material, such as nylon,polyamide, aromatic polyamides, ultra high molecular weight polyethylene(UHMWPE), polyesters, aromatic polyesters, polyethylene terephthalate(PET) or a combination thereof.

In some embodiments, the balloon neck section can be semi-compliant andexpand at different rates than the main balloon body. The neck sectioncompliance can be more, less or equal to the compliance of the balloonbody. Table 2 illustrates example measurements of a balloon that hasneck section that expands more than the balloon body. The expansion rateof the neck diameter can be higher than the expansion rate of thediameter of the main body section in the tested pressure range of 1-5atm. The expansion rate of the neck diameter can be in the range of 1.1to 10 times that of the diameter of the main body section (maindiameter) in the tested pressure range of 1-5 atm, such as in the rangeof 2 to 6 times the main diameter. The expansion rate of the neckdiameter is 12.38% per atm. The expansion rate of the body diameter is2.4% per atm. The difference of the expansion rates is 9.98% per atm.Table 3 illustrates example measurements of a balloon that has a necksection that expands less than the balloon body when inflated from 2atmospheres to 4 atmospheres. The expansion rate of the neck diametercan be less than the expansion rate of the diameter of the main bodysection in the tested pressure range of 2-4 atm.

TABLE 2 Example measurements of a balloon that has neck section thatexpands more than the balloon body. Balloon Neck Body Pressure DiameterDiameter Body Neck [atm] [mm] [mm] Compliance Compliance 1 21.5 39.02.3% (1-2 atm) 12.2% (1-2 atm) 2 24.0 40.0 2.4% (2-3 atm) 15.7% (2-3atm) 3 27.5 40.5 2.6% (3-4 atm) 13.4% (3-4 atm) 4 31.5 41.5 2.3% (4-5atm) 8.2% (4-5 atm) 5 34.0 42.5 — —

TABLE 3 Example measurements of a balloon that has a neck section thatexpands less than the balloon body. Balloon Neck Body Pressure DiameterDiameter Body Neck [atm] [mm] [mm] Compliance Compliance 2 15.28 34.068.7% (2-4 atm) 0.4% (2-4 atm) 4 15.34 37.02 — —

The neck section can create a wedge of tissue between the largerdiameter sections of the balloon that can hold the balloon in place. Thelarger sections of the balloon cannot overcome the tissue barrierscreated at the neck section, thus the balloon with the neck section ispreventing, reducing, or minimizing balloon migration during inflation.Balloon neck sections may be placed at various locations along theballoon, may number more or less than two (e.g., 1, 2, 3, 4, or more),and may vary in diameter. Neck section placement can be designed tofacilitate the greatest increase in traction while still maintainingtreatment efficacy.

The neck section can include a central narrow portion having thesmallest diameter of the neck section, and an adjacent portion that canhave a varying diameter and that occurs between the central narrowportion and portions of the balloon having the main diameter. When thediameter of a neck section is referred to herein, it refers to thediameter of the central narrow portion which has the smallest diameter,and not to the tapered sections, unless otherwise indicated. The taperedsections of the balloon can be rigid, flexible (e.g., elastic), or acombination thereof. The neck section, as measured including the centralnarrow portion and the tapered portions (e.g., cones) adjacent thereto,can have any suitable length, such as about 1% to about 50% of theballoon length, or about 1% or less, or less than, equal to, or greaterthan about 2%, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32,34, 36, 38, 40, 42, 44, 46, 48%, or about 50% or more, or about 0.5 mmto about 40 mm, or about 0.5 mm or less, or less than, equal to, orgreater than about 1 mm, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20,22, 24, 26, 28, 30, 32, 34, 36, 38, or about 40 mm.

In some embodiments, the balloon can include one neck section and isfree of other neck sections, such that the balloon includes two mainsections separated by one neck section. The one neck section can haveany suitable position on the balloon, such as approximately centeredwith respect to the balloon length, or off-center with respect to theballoon length. The one neck section can be off-center with respect tothe length of the balloon and can be at a distal end of the balloon. Anembodiment of the balloon including one neck section that is off-centerwith respect to the length of the balloon is illustrated in FIG. 1A.

In some embodiments, the balloon can include two neck sections and isfree of other neck sections, such that the balloon includes three lobesseparated by two neck sections. The two neck sections can have about thesame diameter, or one of the neck sections can have a smaller diameterthan the other neck sections. The two neck sections can be symmetricallyor asymmetrically located with respect to the center of the balloonlength. The three main sections can have approximately equal length orcan have different lengths. FIG. 1B illustrates an embodiment of aballoon catheter having two neck sections with three main sections,wherein the neck sections are symmetrically located about the center ofthe length of the balloon, and wherein the three main sections of theballoon have about the same length. During use, the distal neck section(e.g., the neck section on the distal end of the balloon catheter whichis inserted into the body first) can anchor and locate the balloon atthe bladder neck, while the proximal neck section can be positioned inthe prostatic urethra. In some embodiments, the distal main section ofthe balloon catheter can be free of the therapeutic agent.

In some embodiments, the balloon can include three necks and is free ofother neck sections, such that the balloon includes four sectionsseparated by the three necks. The three neck sections can be positionedin any suitable way along the length of the balloon. The four mainsections formed by the three neck sections can have equal or differentlengths. The three neck sections can have equal diameters, or differentdiameters. In some embodiments two of the neck sections have an equaldiameter that is smaller than the diameter of the other neck section.FIG. 1C illustrates an embodiment of a balloon catheter having threeneck sections with four main sections each having an approximately equallength, wherein two of the neck sections have an equal diameter that issmaller than the diameter of the other neck section.

The balloon catheter can be a fixed wire balloon catheter. The outershaft can be bonded to the proximal balloon neck, distal end of thetapered wire is bonded with distal neck of balloon, the proximal ends ofthe wire and outer shaft are bonded with the hub (e.g., a valve,connector, or adapter) at the proximal end of the balloon catheter. Theballoon catheter can be a moveable wire catheter. The outer shaft isbonded to proximal balloon neck, the distal end of the tapered wire isbonded with distal neck of balloon, the proximal end of the wire is freeto move relative to the hub at the proximal end of the balloon catheter.The balloon catheter can be an over-the wire balloon catheter. Theballoon catheter can be a rapid exchanged balloon catheter. The ballooncatheter can include a catheter shaft on a longitudinal end of theballoon (e.g., on the proximal end of the balloon, inserted into thebody after insertion of the distal end), the catheter shaft including aninterior lumen for delivery of air, liquid, or a combination thereof, tothe balloon interior. The catheter shaft can include a thermoplasticmaterial that is thermally attached (e.g., attached via heating ormelting) to the balloon, such as a high durometer material, such as amaterial similar or identical to the balloon material, such aspolyamides, nylon (e.g., nylon 6,6, or nylon 12), polyether block amide(PEBA), or a combination thereof. In some embodiments, the cathetershaft can be a scope (e.g., cystoscope). A high durometer material canhelp to prevent, reduce, or minimize crushing, and can allow pushabilityand flexibility. The catheter shaft outer diameter can be sized to allowpassage through the working channel of a standard cystoscope. A fluidicconnection between the inner lumen and the inside of the balloon can beincluded, such as holes in the catheter shaft underneath the balloonattachment point to allow inflation of the balloon by instilling mediathrough the inner lumen.

In various embodiments, the catheter shaft can have a separate lumenwhich creates a pathway for urine to flow from the bladder through thecatheter shaft and out through the external portion of the device. Thisembodiment can allow the drug coated balloon catheter to remain in placefor a period of time, such as 0.1 to about 7 days, while prevention ofbleeding and the tissue healed into the new configuration. The drugcoated balloon not only can be used for dilation and drug delivery alsoused as Foley catheters.

The catheter shaft at an end that remains outside the body (e.g.,proximal end) can include a hub (e.g., a valve, connector, or adapter)that provides a connection to the interior lumen of the catheter shaft.During inflation, the hub (e.g., when closed, or always), can preventbackflow of fluid or air from the balloon. The hub can be can includeany suitable valve, such as a Tuohy Borst adapter. The Tuohy Borstadapter is a compression sealing device that can be placed over thecatheter shaft and tightened to provide a liquid/air tight connection tothe inner lumen of the catheter shaft. A one-way stopcock can allowcontrol over fluid flow into the balloon and can connects via a standardLuer to an inflation device.

The balloon catheter can include a catheter tip at a longitudinal end ofthe balloon, at the distal end which is inserted into the body first.The catheter tip can facilitate passage of the balloon through theurethra. The tip can be an atraumatic tip that helps prevent damage tothe urethra during insertion therein. The tip can be a Coude atraumatictip. The atraumatic Coude tip is designed to facilitate passage of thecatheter through the bends in the male urethra while preventing damageto the urethral walls during tracking. It can be a low durometerbiocompatible material overmolded onto the catheter shaft or adhesivelybonded onto the shaft. For example, the Coude tip can be formed from aPEBAX® or liquid silicone rubber.

FIG. 2 illustrates an embodiment of the balloon catheter including acatheter shaft, catheter tip, and Tuohy Borst adapter/stopcock assembly.All materials can be biocompatible. The balloon is coated with apaclitaxel solution but may be coated with any multitude of other drugsor biologics that could facilitate improvement of BPH symptoms. Only theproximal two main sections of the balloon are coated with drug, sinceduring use the distal section is in the bladder.

The balloon catheter can include an inflation device including apressure gauge or pressure sensor, the inflation device fluidlyconnected to a catheter shaft connected to the balloon catheter.

The balloons shown in FIGS. 1A, 1B, 1C, and 2 are blow molded in a moldthat includes the main sections and the neck sections. A tube of balloonmaterial in inserted into a mold with the desired shape. The balloonmaterial tube may be prestretched. The balloon mold has a shape thatcorresponds to the balloons shown in FIG. 1A, 1B, 1C, or 2. This willinclude a proximal cone, at least one main body section, at least oneneck section, at least one more main body section, and the distal cone.The balloon material can be any of polyesters, polyamides, nylon 12,nylon 11, polyamide 12, block copolymers of polyether and polyamide,PEBAX®, polyurethanes, and block copolymers of polyether and polyester.The tube and mold are heated to a temperature above the glass transitiontemperature of the tube of balloon material and pressurized with gas,air, fluid, or the like resulting in the material of the tube taking theshape of the mold. The formed balloon is then cooled, trimmed, and isthen ready to be attached to the catheter.

After the balloon is attached to a catheter, the balloon is inflated ata low pressure and a neck section reinforcement is attached to the neckregion. The neck section reinforcement is used to control the expansionof the neck section during balloon expansion. The neck section may be asubstantially nonelastic portion of the balloon, a reinforced portion ofthe balloon, or a combination thereof. The neck section can include aninelastic material circulated around a circumference of the necksection, such as a suture or monofilament or multifilaments of suchmaterial, such as steel, stainless steel, nitinol, tungsten, aluminum,copper, silver, gold, platinum, iridium, superalloys contain elements,including nickel (Ni) chromium (Cr), aluminum (Al), titanium (Ti),molybdenum (Mo), tungsten (W), niobium (Nb), tantalum (Ta) and cobalt(Co), nylon, polyamide, aromatic polyamides, ultra high molecular weightpolyethylene (UHMWPE), polyesters, aromatic polyesters, polyethyleneterephthalate (PET) or a combination thereof. In some embodiments, thepolymer material is in strand or filament form and is wrapped numeroustimes around the neck section and then held in place by using two ormore spots of glue or adhesive.

The main sections of the balloon may be formed with identical or similardiameters. In some embodiments, the diameters of the various mainsections may differ from each other by as much as 30%, when measured atnominal balloon diameter. In FIGS. 1A, 1B, 1C, and 2 , the main sectionsof the balloon are shown with equal diameters, that is the diameter ofeach main section is constant. In practice, at higher pressures, thediameter of the main sections will become slightly bowed out, in thatthe diameter of the mid part of the main sections may have a slightlylarger diameter than the edges of the main sections near the ballooncone and/or near the neck sections.

For embodiments where the balloon has neck and main sections, as shownin FIGS. 1A, 1B, 1C, and 2 , and where the balloon doesn't have any necksections, as shown in FIG. 3 , after the balloon catheter is assembled,the balloon may be coated with the at least one water-soluble additiveand drug as discussed herein. In some embodiments where the balloon hasmultiple main sections, the distal main section may not be coated. Theballoon may be coated according to the process discussed herein. If asheath is used, it may be put over the balloon after the balloon iscoated. The catheter is then packaged, sterilized, and labeled as isknown in the art.

Embodiments of the present invention relate to balloon catheters havinga rapid drug-releasing coating and methods for preparing such coateddevices. The therapeutic agent according to embodiments of the presentinvention does not require a delayed or long-term release and instead,for example, the therapeutic agent and the additive are released in avery short time period to provide a therapeutic effect upon contact withtissue. An object of embodiments of the present invention is tofacilitate rapid and efficient uptake of drug by target tissue duringtransitory device deployment at a target site.

The drug coating can cover any suitable proportion of the exteriorsurface of the balloon (e.g., proportion of the surface of the balloonthat obtains the main diameter during inflation to the nominal pressure,excluding necks and end-cones), such as about 1% to about 100%, or about50% to about 100%, to about 80% to about 100%, or about 10% or less, orless than, equal to, or greater than 20%, 30, 40, 50, 60, 70, 75, 80,85, 90, 95, 96, 97, 98, 99, or about 100% or more.

The drug coating can include a water-soluble additive, such as chosenfrom N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof. Thewater-soluble additive can include a first water soluble additive thatis a surfactant such as a PEG sorbitan monolaurate, a PEG sorbitanmonooleate, or a combination thereof. The water-soluble additive caninclude a second water-soluble additive that is a chemical compound withone or more moieties that are hydroxyl, amine, carbonyl, carboxyl, orester, such as sorbitol, sorbitan, xylitol, gluconolactone, or acombination thereof. The drug coating can include both the firstwater-soluble additive and the second water-soluble additive. In someembodiments, the distal end of the balloon can be free of thetherapeutic agent.

In various embodiments, the present invention provides a method fortreating a body lumen. The body lumen can be a vascular body lumen or anonvascular body lumen. The method can include inserting the ballooncatheter (e.g., any embodiment of the balloon catheter described herein)to a target site in the body lumen. The method can include inflating theballoon until (e.g., at least until) the coating layer contacts walls ofthe stricture in the body lumen at the target site and the balloonachieves an inflated balloon diameter for an inflation period. Feature(a), or (b), or (c), or (a) and (b), or (a) and (c), or (b) and (c), or(a) and (b) and (c), are present: (a) the ratio of the inflated balloondiameter to a normative body lumen diameter at the target site is about1.0 to about 20; or (b) the inflating comprises inflating the balloon toa pressure equal to or greater than a nominal pressure of the ballooncatheter, and the stretch ratio of a nominal diameter of the ballooncatheter to a normative body lumen diameter at the target site is about1.0 to about 20; or (c) the inflating comprises inflating to a pressuregreater than the nominal pressure of the balloon catheter, and thenominal diameter of the balloon catheter is less than the inflatedballoon diameter; or (d) a combination of (a), (b), and (c). The methodcan include deflating the balloon after the inflation period. The methodcan include withdrawing the balloon catheter from the stricture in thebody lumen.

Various embodiments provide a method of treating a benign prostatichyperplasia (BPH) stricture, a urethral stricture, a ureteral stricture,prostate cancer, an esophageal stricture, a biliary tract stricture,stomach strictures, small intestine strictures, duodenum strictures,jejunum strictures, ileum strictures, colon strictures, rectumstrictures, and large intestine strictures, asthma, or chronicobstructive pulmonary disease (COPD). The method is a method of treatinga stricture in the body lumen, such as a urethral stricture, a benignprostatic hyperplasia (BPH) stricture, a ureteral stricture, anesophageal stricture, a sinus stricture, stomach strictures, smallintestine strictures, duodenum strictures, jejunum strictures, ileumstrictures, colon strictures, rectum strictures, and large intestinestrictures, and a biliary tract stricture. The stricture in the bodylumen can be a benign prostatic hyperplasia (BPH) stricture, a urethralstructure, or an esophageal stricture. The method can be a method oftreating benign prostatic hyperplasia, prostate cancer, or a combinationthereof, wherein the body lumen is a prostate.

The method can include, prior to, during, or after the insertion of theballoon to the target site, flushing the body lumen with water, salinesolution, or a water solution including at least one water solubleadditive.

The body lumen can be a prostate, wherein inserting the balloon catheterincludes positioning the balloon catheter in the prostate using a scope(e.g., flexible or rigid, such as a cystoscope). The balloon cathetercan include a scope, and the method can include using video feed fromthe scope to locate the target site. The method can include using videofeed from the scope to position the balloon catheter at the target site.

The body lumen can be a prostate, the balloon can have multiple mainsections divided by or more necks, and inserting the balloon cathetercan include positioning one of the balloon catheter main sections in theprostate and positioning a second main section of the balloon catheterin the bladder.

The inserting can include positioning the at least one neck section ofthe balloon in a bladder neck. The at least one neck section of theballoon catheter can be a distal neck section, and the inserting caninclude positioning the distal neck section in the bladder neck. Theballoon catheter can include a proximal neck section, and the insertingcan include positioning the proximal neck section in the prostaticurethra.

The inflation period can be any suitable inflation period, such as about0.1 minutes to about 10 minutes, about 0.5 minutes to about 2 minutes,or about 0.1 minutes or less, or about 0.2 minutes, 0.3, 0.4, 0.5, 0.6,0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.6,2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or about 10 minutes or more.

The inflating can include increasing pressure within the balloon at anysuitable rate (e.g., which can exclude periods wherein pressure dropsdue to tissue yielding and pressure can be maintained during thesetimes), such as about 0.1 atm/minute to about 10 atm/minute, or about0.5 to about 1.5 atm/minute, or about 0.1 atm/minute or less, or lessthan, equal to, or greater than about 0.2 atm/minute, 0.3, 0.4, 0.5,0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4,2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, or about 10 atm/minute or more.

The inflating can include observing the pressure within the balloon,such as via a pressure gauge. During yielding of the stricture, whichcan result in a decrease in pressure, the inflating can include allowingpressure within the balloon to stabilize and maintaining the stabilizedpressure in the balloon for a stabilization period during tissueyielding, then resuming increasing pressure in the balloon until adesired inflation diameter is achieved. The stabilization period can beany suitable period, such as about 0.1 minutes to about 10 minutes,about 0.5 minutes to about 2 minutes, or about 0.1 minutes or less, orabout 0.2 minutes, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3, 3.5, 4, 4.5, 5, 6, 7, 8,9, or about 10 minutes or more.

As shown in FIG. 3 , in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material. The material of balloon 12 caninclude one or more of polyesters, polyamides, nylon 12, nylon 11,polyamide 12, block copolymers of polyether and polyamide, PEBAX®,polyurethanes, and block copolymers of polyether and polyester.

In one embodiment, the present invention provides a balloon catheter fordelivering a therapeutic agent to a tissue, such as a vascular tissue ora nonvascular tissue. The device includes a layer applied to an exteriorsurface of the balloon catheter. The layer includes a therapeutic agentand one or more additives. The additive can be any suitable additive.The layer can include one additive, or the layer can include more thanone additive, such as a water-soluble first additive and a water-solublesecond additive. For example, as shown in the embodiment depicted inFIG. 4A, the balloon 12 is coated with a layer 20 that includes atherapeutic agent and an additive. In some embodiments, the layerconsists essentially of a therapeutic agent and an additive, e.g., thelayer includes only the therapeutic agent and the additive, without anyother materially significant components. In some embodiments, the devicemay optionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 4B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent and anadditive is overlying the adherent layer. The adherent layer, which is aseparate layer underlying the drug coating layer, improves the adherenceof the drug coating layer to the exterior surface of the medical deviceand protects coating integrity. For example, if drug and additive differin their adherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive ratio inthe coating during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid release of coating layer components off the device surface uponcontact with tissues at the target site. In other embodiments, thedevice may include a top layer. For example, as shown in the embodimentdepicted in FIG. 4C, the balloon 12 is coated with an adherent layer 22,a layer 26 that includes a therapeutic agent and an additive overlyingthe adherent layer, and a top layer 28. The top layer may reduce loss ofthe drug layer before it is brought into contact with target tissues,for example during transit of the balloon 12 to the site of therapeuticintervention or during the first moments of inflation of balloon 12before coating layer 20 is pressed into direct contact with targettissue.

Embodiments of the present invention are directed to the treatment ofstrictures in body lumens by delivering of an effective amount oftherapeutic agents, such as anti-inflammatory and antiproliferativedrugs (e.g., rapamycin, paclitaxel, or their analogues). The stricturesin a body lumen include vascular stenosis, urethral strictures, ureteralstrictures, esophageal strictures, achalasia strictures, strictures instents, sinus strictures, stomach strictures, small intestinestrictures, duodenum strictures, jejunum strictures, ileum strictures,colon strictures, rectum strictures, and large intestine strictures, andbiliary tract strictures. Embodiments of the present invention aredirected to methods for treating at least one of vascular stenosis,benign prostatic hyperplasia (BPH), urethral issues, prostate cancer,asthma, and chronic obstructive pulmonary disease (COPD). According toembodiments, the method involves delivering of therapeutic agents suchas anti-inflammatory and antiproliferative drugs (e.g., rapamycin,paclitaxel, or their analogues) via coated medical devices, such asballoon catheters. The therapeutic agent can be coated on the medicaldevice alone or with one or more additives.

In one embodiment, the present invention relates to a method fortreating a stricture in a body lumen including inserting a ballooncatheter including a coating layer into the stricture, wherein thestricture is one of urethral strictures, ureteral strictures, esophagealstrictures, sinus strictures, achalasia strictures, strictures instents, stomach strictures, small intestine strictures, duodenumstrictures, jejunum strictures, ileum strictures, colon strictures,rectum strictures, and large intestine strictures, and biliary tractstrictures, wherein the coating layer includes a drug and an additive,inflating the balloon catheter and releasing the drug to a wall of thestricture, deflating the balloon; and withdrawing the balloon catheter,wherein the residual drug can be about 1 to 70% of the total loadingdrug on the balloon catheter, wherein the drug in the wall of body lumencan be about 0.1 to 25% of the total loading drug on the ballooncatheter. In one aspect of this embodiment, the additive enhancesabsorption of the drug into tissue of the stricture in the body lumen.

In one embodiment, the present invention relates to a method fortreating a stricture of the body lumen including inserting a ballooncatheter including a coating layer into a body lumen, wherein the bodylumen is one of esophagus, airways, sinus, trachea, colon, biliarytract, stomach, small intestine, duodenum, jejunum, ileum, rectum, largeintestine, urinary tract, prostate, urethra, ureter, and other lumens,wherein the coating layer includes a drug and an additive, inflating theballoon catheter and releasing the drug to a wall of the body lumen,deflating the balloon; and withdrawing the balloon catheter, wherein theresidual drug can be about 1 to 70% of the total loading drug on theballoon catheter, wherein the drug in the wall of body lumen can beabout 0.1 to 25% of the total loading drug on the balloon catheter. Inone aspect of this embodiment, the additive enhances absorption of thedrug into tissue of the body lumens. In another aspect of thisembodiment, the additive includes a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has an affinity to the therapeutic agent by hydrogenbonding, and a part that has an affinity to the therapeutic agent by vander Waals interactions.

In one embodiment, the present invention relates to a balloon catheterfor delivering a therapeutic agent to a target site of a body lumenstricture, the balloon catheter including a coating layer overlying anexterior surface of a balloon, wherein the coating layer includes aninitial drug load of a therapeutic agent, and one or more water-solubleadditive; the therapeutic agent is chosen from paclitaxel, docetaxel,taxol, their analogues, rapamycin, sirolimus, everolimus, tacrolimus,and their analogues, and combinations thereof; the water-solubleadditive is chosen from N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

In one embodiment of the balloon catheter, the one or more water-solubleadditives promote a rapid release of the therapeutic agent from theballoon, and whereby the rapid release includes a residual drug amountof the therapeutic agent remaining on the balloon after the balloon isinflated at the target site of the body lumen for an inflation period offrom about 0.1 minutes to 10 minutes and subsequently removed from thebody lumen.

In one embodiment of the balloon catheter, the ratio by weight of thetherapeutic (e.g., hydrophobic) agent in the coating layer to the totalweight of the one or more additives in the coating layer can be about0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5, about 0.5to about 8, about 0.5 to about 3, about 2 to about 6, or about 0.05 orless, or less than, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 or more. Inone embodiment of the balloon catheter, the ratio by weight of thetherapeutic agent in the coating layer to the total weight of the one ormore water-soluble additives (e.g., a first and second water solubleadditive in the coating layer, or to the total weight of a first,second, and third water soluble additive) in the coating layer, is fromabout 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5,about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or about0.05 or less, or less than, equal to, or greater than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 ormore.

In one embodiment, the present invention relates to a method fortreating a stricture in a body lumen, the method including flushing thebody lumen with water, saline solution, or a water solution including atleast one water soluble additive; inserting a balloon catheter into atarget site in the stricture in the body lumen, the balloon catheterincluding a balloon and a coating layer overlying external surfaces ofthe balloon. The coating layer includes at least one water-solubleadditive, and an initial drug load of a therapeutic agent; thetherapeutic agent is chosen from paclitaxel, docetaxel, taxol, theiranalogues, rapamycin, sirolimus, everolimus, tacrolimus, theiranalogues, and combinations thereof; the water-soluble additive ischosen from N-acetylglucosamine, N-octyl-D-gluconamide,N-Nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine C6-ceramide,dihydro-C6-ceramide, cerabroside, sphingomyelin, galaclocerebrosides,lactocerebrosides, N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate, PEG caprate, PEG caproate, glyceryl monocaprylate, glycerylmonocaprate, glyceryl monocaproate, monolaurin, monocaprin,monocaprylin, monomyristin, monopalmitolein, monoolein, creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl) urea, pentaerythritol ethoxylate,pentaerythritol propoxylate, pentaerythritol propoxylate/ethoxylate,glycerol ethoxylate, glycerol propoxylate, trimethylolpropaneethoxylate, pentaerythritol, dipentaerythritol, crown ether, 18-crown-6,15-crown-5, 12-crown-4, and combinations thereof; inflating the balloonuntil the coating layer contacts walls of the stricture in the bodylumen at the target site and the balloon achieves an inflated balloondiameter for an inflation period; deflating the balloon after theinflation period, wherein the inflation period is from 0.1 minutes to 10minutes; and withdrawing the balloon catheter from the stricture in thebody lumen. The inflated balloon catheter diameter can be such that theratio of the inflated balloon diameter to a normative diameter of thetreated body lumen can be about 1.0 to about 20, or about 1.1 to about15, or about 1.2 to about 10, or about 1.0 or less, or less than, equalto, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3,4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more; the stretchratio of the nominal balloon diameter to the normative diameter of thebody lumen at the location of treatment can be about 1.0 to about 20, orabout 1.1 to about 15, or about 1.2 to about 10, or about 1.0 or less,or less than, equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20or more. Optionally the inflating can include inflating to a pressureequal to or greater than the nominal pressure of the balloon catheter.

The balloon can have thereon a residual drug amount after thewithdrawing. Any suitable residual drug amount can remain after thewithdrawing, such as greater than, equal to, or less than about 90 wt %,88, 86, 84, 82, 80, 78, 76, 74, 72, 70, 68, 66, 64, 62, 60, 58, 56, 54,52, 50, 48, 46, 44, 42, 40, 38, 36, 34, 32, 30, 28, 26, 24, 22, 20, 18,16, 14, 12, 10, 8, 6, 4, 3, 2, 1 wt %, or about 0 wt %.

In one embodiment, the present invention relates to a method fortreating at least one of a benign prostatic hyperplasia and prostatecancer, the method including flushing the prostate with water, salinesolution, or a water solution including at least one water solubleadditive; inserting a balloon catheter into a target site in theprostate, the balloon catheter including a balloon and a coating layeroverlying external surfaces of the balloon. The coating layer caninclude one or more water-soluble additives, and an initial drug load ofa therapeutic agent; inflating the balloon until the coating layercontacts walls of the benign prostatic hyperplasia or prostate cancer atthe target site and the balloon achieves an inflated balloon diameterfor an inflation period; deflating the balloon after the inflationperiod, wherein the inflation period is from 0.1 minutes to 10 minutes;and withdrawing the balloon catheter from the prostate. The ratio of theinflated balloon diameter to a normative diameter of the body lumen canbe about 1.0 to about 20, or about 1.01 to about 15, or about 1.01 orless, or less than, equal to, or greater than about 1.01, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more; the stretch ratio of the nominal balloon diameter to thenormative diameter of the body lumen at the location of treatment can beabout 1.0 to about 20, or about 1.1 to about 15, or about 1.2 to about10, or about 1.0 or less, or less than, equal to, or greater than about1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12,14, 16, 18, or about 20 or more. Optionally the inflating can includeinflating to a pressure equal to or greater than the nominal pressure ofthe balloon catheter.

In one embodiment, the present invention relates to a method fortreating a urethral stricture, the method including flushing theurethral stricture with water, saline solution, or a water solutionincluding at least one water soluble additive; inserting a ballooncatheter into a target site in the urethral stricture, the ballooncatheter including a balloon and a coating layer overlying externalsurfaces of the balloon, wherein the coating layer includes at least onewater-soluble additive, and an initial drug load of a therapeutic agent;and the ratio by weight of the therapeutic agent in the coating layer tothe total weight of the one or more water-soluble additives in thecoating layer is from about 0.05 to 20; inflating the balloon until thecoating layer contacts walls of the urethral stricture at the targetsite and the balloon achieves an inflated balloon diameter for aninflation period; deflating the balloon after the inflation period,wherein the inflation period is from 0.1 minutes to 10 minutes; andwithdrawing the balloon catheter from the urethral stricture. The ratioof the inflated balloon diameter to a normative diameter of the urethrain the location of the stricture can be about 1.0 to about 20, or about1.01 to about 15, or about 1.01 or less, or less than, equal to, orgreater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 14, 16, 18, or about 20 or more; the stretch ratio of thenominal balloon diameter to the normative diameter of the body lumen atthe location of treatment can be about 1.0 to about 20, or about 1.1 toabout 15, or about 1.2 to about 10, or about 1.0 or less, or less than,equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more. Afterdilation, the diameter of the urethral stricture can be 6.7 mm or more,such as about 6.7 mm to about 50 mm, or about 6.7 mm to about 20 mm, orless than, equal to, or greater than about 6.7, 6.8, 6.9, 7.0, 7.2, 7.4,7.6, 7.8, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,25, 30, 35, 40, 45 mm, or about 50 mm or more. Optionally the inflatingcan include inflating to a pressure equal to or greater than the nominalpressure of the balloon catheter.

In one embodiment, the present invention relates to a method fortreating an esophageal stricture such as an achalasia stricture, themethod including optionally flushing the esophageal stricture prior to,during, or after insertion of the balloon catheter with water, salinesolution or a water solution including at least one water solubleadditive; inserting a balloon catheter into a target site in theesophageal stricture, the balloon catheter including a balloon and acoating layer overlying external surfaces of the balloon, wherein thecoating layer includes at least one water-soluble second additive, and atherapeutic agent with an initial drug load of from 1 to 6 micrograms ofthe therapeutic agent per square millimeter of the balloon at itsnominal diameter; and the ratio by weight of the therapeutic agent inthe coating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 0.05 to 20; inflating theballoon until the coating layer contacts walls of the esophagealstricture at the target site and the balloon achieves an inflatedballoon diameter for an inflation period; deflating the balloon afterthe inflation period, wherein the inflation period is from 0.1 minutesto 10 minutes; and withdrawing the balloon catheter from the esophagealstricture. The ratio of the balloon diameter to a normative diameter ofthe esophagus at the location of the stricture can be about 1.0 to about20, or about 1.01 to about 20, or about 1.01 or less, or less than,equal to, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3,4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more; the stretchratio of the nominal balloon diameter to the normative diameter of theesophagus at the location of the stricture can be about 1.0 to about 20,or about 1.1 to about 15, or about 1.2 to about 10, or about 1.0 orless, or less than, equal to, or greater than about 1.01, 1.1, 1.2, 1.3,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more. In some embodiments, the balloon catheter properties areequal or similar to those given in Table 4, having a growth rate thatslows at higher pressures. Compliance is the percent change in balloondiameter from nominal diameter to rated burst pressure (RBP) diameter,calculated as: Diameter @ RBP−Diameter @ nominal pressure)/Diameter @nominal pressure)*100%. Optionally the inflating can include inflatingto a pressure equal to or greater than the nominal pressure of theballoon catheter.

TABLE 4 Examples of properties of balloon catheters for treatingesophageal and gastrointestinal strictures. Nominal Rated burst NominalRated burst diameter pressure pressure pressure Compliance (mm) diameter(mm) (atm) (atm) (%) 4 6 3 12 50 6 8 3 10 30 8 10 3 9 25 10 12 3 8 20 1215 3 8 17 15 18 3 7 20 18 20 3 6 11 20 23 3 6 15 23 25 3 6 9 30 34 2 413 35 40 2 4 14 40 45 2 4 12

In one embodiment, the present invention relates to a method fortreating an esophageal stricture such as an achalasia stricture, themethod including flushing the esophageal stricture with water, salinesolution or a water solution including at least one water solubleadditive optionally prior to, during, after insertion of ballooncatheter; inserting a balloon catheter into a target site in theesophageal stricture, the balloon catheter including a balloon and acoating layer overlying external surfaces of the balloon, wherein thecoating layer includes at least one water-soluble second additive, and atherapeutic agent with an initial drug load of from 1 to 6 micrograms ofthe therapeutic agent per square millimeter of the balloon at itsnominal diameter; and the ratio by weight of the therapeutic agent inthe coating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 0.05 to 20; inflating theballoon until the coating layer contacts walls of the esophagealstricture at the target site and the balloon achieves an inflatedballoon diameter for an inflation period; deflating the balloon afterthe inflation period, wherein the inflation period is from 0.1 minutesto 10 minutes; and withdrawing the balloon catheter from the esophagealstricture. The ratio of the inflated balloon diameter to a normativediameter of the esophagus at the location of the stricture can be about1.0 to about 20, or about 1.01 to about 20, or about 1.31 to 20, orabout 1.01 or less, or less than, equal to, or greater than about 1.1,1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14,16, 18, or about 20 or more; the stretch ratio of the nominal balloondiameter to the normative diameter of the esophagus at the location ofthe stricture can be about 1.0 to about 20, or about 1.1 to about 15, orabout 1.2 to about 10, or about 1.31 to 20, or about 1.0 or less, orless than, equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.31,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more. Optionally the inflating can include inflating to a pressureequal to or greater than the nominal pressure of the balloon catheter.In some embodiments, the balloon catheter properties are equal orsimilar to those given in Table 5, a single balloon catheter having theability to achieve a wide range of balloon diameters at relatively highworking pressures compared to conventional compliant balloons. Balloonsin Table 5 have a unique feature that there are three increasing balloondiameters at three increasing inflation pressure stages. The nominalinflation diameter is the diameter at stage I. The diameter increasesabout 0.5-4 mm, preferably 0.75-3 mm, most preferably 0.9-2 mm for everystage of pressure increase. For example, a balloon that has a diameterof 15 mm at Pressure I (3 ATM) has a diameter of 16.5 mm at pressure II(4.5 ATM) and has a diameter of 18 mm at pressure III (7 ATM).

TABLE 5 Examples of properties of balloon catheters for treatingesophageal and gastrointestinal strictures. Diameter at Diameter atDiameter at pressure pressure pressure Three inflation stage I (mm)stage II stage III pressure stages (atm) [Nominal Diameter] (mm) (mm) 3,6, 10 4 5 6 3, 6, 10 6 7 8 3, 5.5, 9 8 9 10 3, 5, 8 10 11 12 3, 4.5, 812 13.5 15 3, 4.5, 7 15 16.5 18 3, 4.5, 6 18 19 20 3, 4.5, 5.5 20 21.523 3, 4, 5 23 24 25 2, 3.5, 4.5 30 32.5 35 2, 3, 4 35 37.5 40 2, 3, 4 4042.5 45

In one embodiment, the present invention relates to a method fortreating an gastrointestinal strictures, the gastrointestinal stricturesinclude stomach strictures, small intestine strictures, duodenumstrictures, jejunum strictures, ileum strictures, colon strictures,rectum strictures, and large intestine strictures and biliary tractstrictures, the method including flushing the gastrointestinal stricturewith water, saline solution or a water solution including at least onewater soluble additive; inserting a balloon catheter into a target sitein the gastrointestinal stricture, the balloon catheter including aballoon and a coating layer overlying external surfaces of the balloon,wherein the coating layer includes at least one water-soluble secondadditive, and a therapeutic agent with an initial drug load of from 1 to6 micrograms of the therapeutic agent per square millimeter of theballoon at its nominal diameter; and the ratio by weight of thetherapeutic agent in the coating layer to the total weight of the one ormore water-soluble additives in the coating layer is from about 0.05 to20; inflating the balloon until the coating layer contacts walls of theesophageal stricture at the target site and the balloon achieves aninflated balloon diameter for an inflation period; deflating the balloonafter the inflation period, wherein the inflation period is from 0.1minutes to 10 minutes; and withdrawing the balloon catheter from theesophageal stricture. The inflated balloon catheter diameter can be suchthat the ratio of the balloon diameter to a normative diameter of theesophagus at the location of the stricture can be about 1.0 to about 20,or about 1.31 to about 20, or about 1.01 to about 15, or about 1.01 orless, or less than, equal to, or greater than about 1.1, 1.2, 1.3, 1.31,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more; the stretch ratio of the nominal balloon diameter to thenormative diameter of the esophagus at the location of the stricture canbe about 1.0 to about 20, or about 1.31 to about 20, or about 1.1 toabout 15, or about 1.2 to about 10, or about 1.0 or less, or less than,equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5,1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 ormore. Optionally the inflating can include inflating to a pressure equalto or greater than the nominal pressure of the balloon catheter. In someembodiments, the balloon catheter has properties are that are equal orsimilar to those given in Tables 4 and 5, having a growth rate thatslows at higher pressures and a single balloon catheter having theability to achieve a wide range of balloon diameters at high workingpressures.

In various embodiments, the drug coated balloon catheters used to treatthe esophageal strictures, achalasia stricture, gastrointestinalstrictures, the gastrointestinal strictures include stomach strictures,small intestine strictures, duodenum strictures, jejunum strictures,ileum strictures, colon strictures, rectum strictures, and largeintestine strictures and biliary tract strictures, have a catheterdesign that is fixed wire, wire-guided, over the wire catheter, or rapidexchange design catheters.

In one embodiment, the present invention relates to a method fortreating a sinus stricture, the method including: flushing the sinusstricture with water, saline solution, or a water solution including atleast one water soluble additives; inserting a balloon catheter into atarget site in the sinus stricture, the balloon catheter including aballoon and a coating layer overlying external surfaces of the balloon,wherein the coating layer includes at least one water-soluble additive,and a therapeutic agent with an initial drug load of from 1 to 6micrograms of the therapeutic agent per square millimeter of the balloonat its nominal diameter; the therapeutic agent is chosen frombudesonide, flunisolide, triamcinolone, beclomethasone, fluticasone,mometasone, mometasone furoate, dexamethasone, hydrocortisone,methylprednisolone, prednisone, cortisone, betamethasone, triamcinoloneacetonide, and combinations thereof; the water-soluble additive ischosen from N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the therapeutic agent in the coating layer to thetotal weight of the one or more water-soluble additives in the coatinglayer is from about 0.05 to 20; inflating the balloon until the coatinglayer contacts walls of the sinus stricture at the target site and theballoon achieves an inflated balloon diameter for an inflation period;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the sinus stricture.

In some embodiments, it may be desirable to predilate the target regionof the body lumen, such as the prostate, prior to using the drug coatedballoon. In some embodiments, the predilation balloon is selected to beslightly shorter and/or have a slightly smaller nominal diameter thanthe treatment balloon. If the predilation balloon is shorter than thetreatment balloon, it will be more likely that the entire predilatedzone or region gets treated by the treatment balloon. In someembodiments, it may be desirable to dilate the target region of the bodylumen directly without predilation.

Embodiments of the present invention relate to balloon catheters havinga rapid drug-releasing coating and methods for preparing such coateddevices. The therapeutic agent according to embodiments of the presentinvention does not require a delayed or long-term release and instead,for example, the therapeutic agent and the additive are released in avery short time period to provide a therapeutic effect upon contact withtissue. An object of embodiments of the present invention is tofacilitate rapid and efficient uptake of drug by target tissue duringtransitory device deployment at a target site.

In various embodiments, the balloon catheter can have 1 to or multiple(e.g., 2) neck sections along the body of the balloon. Neck sectionshave smaller nominal diameters than the nominal balloon body diameter(e.g., 1.5 to 2.5× smaller) and can be any suitable length, such asabout 10-20 mm long. Neck sections can divide the balloon symmetricallyor can result in certain balloon body sections being longer than others.Nominal balloon diameters can range from 6-45 mm with working lengths of20 to 160 mm.

In FIG. 1A, in one embodiment, a balloon with one neck section is shown.Balloon 100, has waist 101, cone 102, first body section 103, neck 104,second body section 105, cone 106, and waist 107. When assembled into aballoon catheter, as is known in the art, waists 101 and 107 will beattached or bonded or the like to the catheter shaft (not shown). Duringinflation, waists 101 and 107 do not inflate as they are attached to thecatheter shaft. In FIG. 1B, in one embodiment, a balloon with two necksections is shown. Balloon 120, has waist 121, cone 122, first bodysection 123, first neck 124, second body section 125, second neck 126,third body section 127, cone 128, and waist 129. When assembled into aballoon catheter, as is known in the art, waists 121 and 129 will beattached or bonded or the like to the catheter shaft. During inflation,waists 121 and 129 do not inflate as they are attached to the cathetershaft. While neck sections 124 and 126 are shown as being the samediameter at the present state of inflation, they can be the same ordifferent diameters with the same or different compliance. In FIG. 1C,in one embodiment, a balloon with three neck sections is shown. Balloon140, has waist 141, cone 142, first body section 143, first neck 144,second body section 145, second neck 146, third body section 147, thirdneck 148, fourth body section 149, cone 150, and waist 151. Whenassembled into a balloon catheter, as is known in the art, waists 141and 151 will be attached or bonded or the like to the catheter shaft.During inflation, waists 141 and 151 do not inflate as they are attachedto the catheter shaft. While neck sections 144, 146, and 148 are shownwith different diameters at the present state of inflation, they can bethe same or different diameters with the same of different compliance.

As shown in FIG. 2 , in one embodiment, the medical device is a ballooncatheter, a fixed wire balloon catheter, a moveable wire catheter, anover the wire balloon catheter, a rapid exchanged balloon catheter,including conventional balloon catheters known to one of ordinary skillin the art. For example, balloon catheter 150 may include an expandable,inflatable balloon at a distal end of the catheter 150, a handleassembly 160 at a proximal end of the catheter 150, an elongate flexiblemember 164 extending between the proximal and distal ends, andatraumatic Coude tip 163. Handle assembly 160 may connect to and/orreceive one or more suitable medical devices, such as a source ofinflation media (e.g., air, saline, or contrast media). Flexible member164 may be a tube made of suitable biocompatible material and having oneor more lumens therein. At least one of the lumens is configured toreceive inflation media and pass such media to balloon 162 for itsexpansion. The balloon catheter may be a fixed wire or a rapid exchangeor over-the-wire catheter and made of any suitable biocompatiblematerial. The material of balloon 162 can include one or more ofpolyesters, polyamides, nylon 12, nylon 11, polyamide 12, blockcopolymers of polyether and polyamide, PEBAX®, polyurethanes, and blockcopolymers of polyether and polyester. In FIG. 2 , in one embodiment, aballoon with two neck sections is shown. Balloon 162, has waist 151,cone 152, first body section 153, first neck 154, second body section155, second neck 156, third body section 157, cone 158, and waist 159.When assembled into a balloon catheter, as is known in the art, waists151 and 159 will be attached or bonded or the like to the cathetershaft. During inflation, waists 151 and 159 do not inflate as they areattached to the catheter shaft. While neck sections 154 and 156 areshown as being the same diameter at the present state of inflation, theycan be the same or different diameters with the same or differentcompliance.

As shown in FIG. 3 , in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including a fixed wire balloon catheter, a moveable wirecatheter, an over the wire balloon catheter, a rapid exchanged ballooncatheter, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material. The material of balloon 12 caninclude one or more of polyesters, polyamides, nylon 12, nylon 11,polyamide 12, block copolymers of polyether and polyamide, PEBAX®,polyurethanes, and block copolymers of polyether and polyester.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a diseased tissue or stricture, suchas a vascular tissue or a nonvascular tissue. The device includes alayer applied to an exterior surface of the balloon catheter. The layerincludes a therapeutic agent and one or more additives. The additive canbe any suitable additive. The layer can include one additive, or thelayer can include more than one additive, such as a water-soluble firstadditive and a water-soluble second additive. For example, as shown inthe embodiment depicted in FIG. 4A, the balloon 12 is coated with alayer 20 that includes a therapeutic agent and an additive. In someembodiments, the layer consists essentially of a therapeutic agent andan additive, e.g., the layer includes only the therapeutic agent and theadditive, without any other materially significant components. In someembodiments, the device may optionally include an adherent layer. Forexample, as shown in the embodiment depicted in FIG. 4B, the balloon 12is coated with an adherent layer 22. A layer 24 that includes atherapeutic agent and an additive is overlying the adherent layer. Theadherent layer, which is a separate layer underlying the drug coatinglayer, improves the adherence of the drug coating layer to the exteriorsurface of the medical device and protects coating integrity. Forexample, if drug and additive differ in their adherence to the medicaldevice, the adherent layer may prevent differential loss of componentsand maintain drug-to-additive ratio in the coating during transit to atarget site for therapeutic intervention. Furthermore, the adherentlayer may function to facilitate rapid release of coating layercomponents off the device surface upon contact with tissues at thetarget site. In other embodiments, the device may include a top layer.The top layer may reduce loss of the drug layer before it is broughtinto contact with target tissues, for example during transit of theballoon 12 to the site of therapeutic intervention or during the firstmoments of inflation of balloon 12 before coating layer 20 is pressedinto direct contact with target tissue.

Embodiments of the present invention are directed to the treatment ofstrictures in nonvascular body lumens by delivering of an effectiveamount of a therapeutic agent such as anti-inflammatory andantiproliferative drugs (e.g., rapamycin, sirolimus, everolimus,tacrolimus, paclitaxel, taxol, docetaxel or their analogues). Thestrictures in a nonvascular body lumen include urethral strictures,ureteral strictures, esophageal strictures, sinus strictures, achalasiastrictures, strictures in stents, stomach strictures, small intestinestrictures, duodenum strictures, jejunum strictures, ileum strictures,colon strictures, rectum strictures, and large intestine strictures andbiliary tract strictures. Embodiments of the present invention aredirected to methods for treating at least one of benign prostatichyperplasia (BPH), prostate cancer, asthma, and chronic obstructivepulmonary disease (COPD). According to various embodiments, the methodinvolves delivering of a therapeutic agent such as anti-inflammatory andantiproliferative drugs (e.g., rapamycin, sirolimus, everolimus,tacrolimus, paclitaxel, taxol, docetaxel, or their analogues) via coatedballoon catheters. The anti-inflammatory and antiproliferative drugs canbe coated on the medical device alone or with one or more additives.

A method for treating a stricture in a nonvascular body lumen includesinserting a balloon catheter including a coating layer into a bodylumen, wherein the coating layer includes a drug and an additive,inflating the balloon catheter and releasing the drug to a wall of thenonvascular body lumen, deflating the balloon; and withdrawing theballoon catheter, wherein the residual drug can be about 1 to 70% of thetotal loading drug on the balloon catheter, wherein the drug in the wallof body lumen can be about 0.1 to 25% of the total loading drug on theballoon catheter. The method can include, prior to, during, or after theinsertion of the balloon to the target site, flushing the body lumenwith water, saline solution, or a water solution including at least onewater soluble additive. In one aspect of this embodiment, the additiveenhances absorption of the drug into tissue of the nonvascular bodylumens. In another aspect of this embodiment, the additive includes ahydrophilic part and a drug affinity part, wherein the drug affinitypart is at least one of a hydrophobic part, a part that has an affinityto the therapeutic agent by hydrogen bonding, and a part that has anaffinity to the therapeutic agent by van der Waals interactions.

A balloon catheter for delivering a therapeutic agent to a target siteof a nonvascular body lumen can include a coating layer overlying anexterior surface of a balloon, wherein the coating layer includes aninitial drug load of a therapeutic agent, and one or more water-solubleadditive; the therapeutic agent is chosen from paclitaxel, taxol,docetaxel, their analogues, rapamycin, sirolimus, everolimus, and theiranalogues, and combinations thereof; the water-soluble additive ischosen from N-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

The nonvascular body lumen can be one of esophagus, airways, sinus,trachea, colon, biliary tract, stomach, small intestine, duodenum,jejunum, ileum, rectum, large intestine, urinary tract, prostate,urethra, ureter, and other nonvascular lumens.

In some embodiments, the one or more water-soluble additives can promotea rapid release of the therapeutic agent from the balloon, and wherebythe rapid release includes a residual drug amount of the therapeuticagent remaining on the balloon after the balloon is inflated at thetarget site of the nonvascular body lumen for an inflation period offrom about 0.1 minutes to 10 minutes and subsequently removed from thenonvascular lumen.

The ratio by weight of the therapeutic agent in the coating layer to thetotal weight of the one or more additives in the coating layer can beabout 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5,about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or about0.05 or less, or less than, equal to, or greater than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 ormore. The ratio by weight of the therapeutic agent in the coating layerto the total weight of the one or more water-soluble additives (e.g., afirst and second water soluble additive in the coating layer, or to thetotal weight of a first, second, and third water soluble additive) inthe coating layer, can be from about 0.05 to about 20, about 0.1 toabout 10, about 0.1 to about 5, about 0.5 to about 8, about 0.5 to about3, about 2 to about 6, or about 0.05 or less, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or about 20 or more.

The initial drug load can be from 1 microgram to 20 micrograms of thetherapeutic agent per square millimeter of the balloon (i.e., perexternal surface area of the nominal diameter of the balloon), or about2 to about 6 micrograms, or about 1 microgram or less, or less than,equal to, or greater than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16,18, or about 20 micrograms or more. The residual drug amount can be 70%or less of the initial drug load.

A method for treating a stricture in a nonvascular body lumen includesflushing the nonvascular body lumen with water, saline solution, or awater solution including at least one water soluble additive; insertinga balloon catheter into a target site in the stricture in thenonvascular body lumen, the balloon catheter including a balloon and acoating layer overlying external surfaces of the balloon. The coatinglayer includes a at least one water-soluble additive, and an initialdrug load of a therapeutic agent; the therapeutic agent is chosen frompaclitaxel, taxol, docetaxel, their analogues, rapamycin, sirolimus,everolimus, and their analogues, and combinations thereof; thewater-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-Nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-Lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl) urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof;inflating the balloon until the coating layer contacts walls of thestricture in the nonvascular body lumen at the target site and theballoon achieves an inflated balloon diameter for an inflation period;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the stricture in the nonvascular body lumen. In someembodiments, the balloon diameter is 10 mm at the nominal inflationpressure of 6 atm. The ratio of the inflated balloon diameter to anormative diameter of the target site of the body lumen can be about1.01 to about 20; the stretch ratio of the nominal balloon diameter tothe normative diameter of the body lumen at the location of thetreatment can be about 1.0 to about 20, or about 1.1 to about 15, orabout 1.2 to about 10, or about 1.0 or less, or less than, equal to, orgreater than about 1.01, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5,6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more. Optionally theinflating can include inflating to a pressure equal to or greater thanthe nominal pressure of the balloon catheter.

The balloon can have thereon a residual drug amount after thewithdrawing. Any suitable residual drug amount can remain after thewithdrawing, such as greater than, equal to, or less than about 70 wt %,65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5 wt %, or about 0 wt %.

The ratio by weight of the therapeutic agent in the coating layer to thetotal weight of the one or more additives in the coating layer can beabout 0.05 to about 20, about 0.1 to about 10, about 0.1 to about 5,about 0.5 to about 8, about 0.5 to about 3, about 2 to about 6, or about0.05 or less, or less than, equal to, or greater than about 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or about 20 ormore.

In various embodiments, the coating layer can include one or morewater-soluble additives, and an initial drug load of a therapeuticagent; the therapeutic agent is chosen from paclitaxel, paclitaxelanalogues, rapamycin, rapamycin analogues, and combinations thereof; thewater-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

A method for treating at least one of a benign prostatic hyperplasia andprostate cancer can include flushing the prostate with water, salinesolution, or a water solution including at least one water solubleadditive; inserting a balloon catheter into a target site in theprostate, the balloon catheter including a balloon and a coating layeroverlying external surfaces of the balloon. The method can includeinflating the balloon until the coating layer contacts walls of thebenign prostatic hyperplasia or prostate cancer at the target site andthe balloon achieves an inflated balloon diameter for an inflationperiod; deflating the balloon after the inflation period, wherein theinflation period is from 0.1 minutes to 10 minutes; and withdrawing theballoon catheter from the prostate. The ratio of inflated balloondiameter to normative body lumen diameter at the target site can beabout 1.01 to about 20, or about 1.31 to about 20, or about 1.1 to about15, or about 1.2 to about 10, or greater than about 1.1, 1.2, 1.3, 1.31,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more; the stretch ratio of the nominal balloon diameter to thenormative diameter of the body lumen at the location of the treatmentcan be about 1.0 to about 20, or about 1.31 to about 20, or about 1.1 toabout 15, or about 1.2 to about 10, or about 1.0 or less, or less than,equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5,1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 ormore. Optionally the inflating can include inflating to a pressure equalto or greater than the nominal pressure of the balloon catheter.

A method for treating a urethral stricture includes flushing theurethral stricture with water, saline solution, or a water solutionincluding at least one water soluble additive; inserting a ballooncatheter into a target site in the urethral stricture, the ballooncatheter including a balloon and a coating layer overlying externalsurfaces of the balloon, wherein the coating layer includes at least onewater-soluble additive, and an initial drug load of a therapeutic agent;and the ratio by weight of the therapeutic agent in the coating layer tothe total weight of the one or more water-soluble additives in thecoating layer is from about 0.05 to 20; inflating the balloon until thecoating layer contacts walls of the urethral stricture at the targetsite and the balloon achieves an inflated balloon diameter for aninflation period; deflating the balloon after the inflation period,wherein the inflation period is from 0.1 minutes to 10 minutes; andwithdrawing the balloon catheter from the urethral stricture. The ratioof inflated balloon diameter to a normative diameter of the body lumenat the site of the urethral stricture can be about 1.01 to about 20, orabout 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about10, or greater than about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5,6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more; the stretch ratioof the nominal balloon diameter to the normative diameter of the bodylumen at the location of the treatment can be about 1.0 to about 20, orabout 1.31 to about 20, or about 1.1 to about 15, or about 1.2 to about10, or about 1.0 or less, or less than, equal to, or greater than about1.01, 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 14, 16, 18, or about 20 or more. After dilation, the diameter ofthe urethral stricture can be 6.7 mm or more, such as about 6.7 mm toabout 50 mm, or about 6.7 mm to about 20 mm, or less than, equal to, orgreater than about 6.7, 6.8, 6.9, 7.0, 7.2, 7.4, 7.6, 7.8, 8, 8.5, 9,9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45 mm,or about 50 mm or more. Optionally the inflating can include inflatingto a pressure equal to or greater than the nominal pressure of theballoon catheter.

In one embodiment, the balloon has thereon a residual drug amount ofless than 70% of the initial drug load after the withdrawing.

A method for treating an esophageal stricture includes flushing theesophageal stricture with water, saline solution or a water solutionincluding at least one water soluble additive; inserting a ballooncatheter into a target site in the esophageal stricture, the ballooncatheter including a balloon and a coating layer overlying externalsurfaces of the balloon, wherein the coating layer includes at least onewater-soluble second additive, and a therapeutic agent with an initialdrug load of from 1 to 6 micrograms of the therapeutic agent per squaremillimeter of the balloon; the therapeutic agent is chosen frompaclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus,everolimus, mTOR inhibitors, or their analogues, and combinationsthereof; the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the therapeutic agent in the coating layer to thetotal weight of the one or more water-soluble additives in the coatinglayer is from about 0.05 to 20; inflating the balloon until the coatinglayer contacts walls of the esophageal stricture at the target site andthe balloon achieves an inflated balloon diameter for an inflationperiod; deflating the balloon after the inflation period, wherein theinflation period is from 0.1 minutes to 10 minutes; and withdrawing theballoon catheter from the esophageal stricture. The ratio of theinflated balloon diameter to the normative diameter of the esophagus atthe location of the stricture can be about 1.01 to about 20, 1.31 to 20,or about 1.1 to about 15, or about 1.3 to about 10, or about 1.31 to 10,or about or greater than about 1.1, 1.2, 1.3, 1.31, 1.4, 1.5, 1.6, 1.8,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 or more; thestretch ratio of the nominal balloon diameter to the normative diameterof the body lumen at the location of the treatment can be about 1.0 toabout 20, 1.31 to 20, or about 1.1 to about 15, or about 1.2 to about10, or about 1.3 to 10, or about 1.31 to 10, or about 1.0 or less, orless than, equal to, or greater than about 1.01, 1.1, 1.2, 1.3, 1.31,1.4, 1.5, 1.6, 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about20 or more. Optionally the inflating can include inflating to a pressureequal to or greater than the nominal pressure of the balloon catheter.

A method for treating a sinus stricture includes flushing the sinusstricture with water, saline solution, or a water solution including atleast one water soluble additives; inserting a balloon catheter into atarget site in the sinus stricture, the balloon catheter including aballoon and a coating layer overlying external surfaces of the balloon,wherein the coating layer includes at least one water-soluble additive,and a therapeutic agent with an initial drug load of from 1 to 6micrograms of the therapeutic agent per square millimeter of theballoon; the therapeutic agent is chosen from budesonide, flunisolide,triamcinolone, beclomethasone, fluticasone, mometasone, mometasonefuroate, dexamethasone, hydrocortisone, methylprednisolone, prednisone,cotisone, betamethasone, triamcinolone acetonide, and combinationsthereof; the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof; andthe ratio by weight of the therapeutic agent in the coating layer to thetotal weight of the one or more water-soluble additives in the coatinglayer is from about 0.05 to 20; inflating the balloon until the coatinglayer contacts walls of the sinus stricture at the target site and theballoon achieves an inflated balloon diameter for an inflation period;deflating the balloon after the inflation period, wherein the inflationperiod is from 0.1 minutes to 10 minutes; and withdrawing the ballooncatheter from the sinus stricture.

Additive.

In various embodiments, the additive can have two parts. One part ishydrophilic and the other part is a drug affinity part. The drugaffinity part is a hydrophobic part and/or has an affinity to thetherapeutic agent by hydrogen bonding and/or van der Waals interactions.The drug affinity part of the additive may bind the lipophilic drug,such as rapamycin or paclitaxel. The hydrophilic portion acceleratesdiffusion and increases permeation of the drug into tissue. It mayfacilitate rapid movement of drug off the medical device duringdeployment at the target site by preventing hydrophobic drug moleculesfrom clumping to each other and to the device, increasing drugsolubility in interstitial spaces, and/or accelerating drug lumenthrough polar head groups to the lipid bilayer of cell membranes oftarget tissues. The additives of embodiments of the present inventionhave two parts that function together to facilitate rapid release ofdrug off the device surface and uptake by target tissue duringdeployment (by accelerating drug contact with tissues for which drug hashigh affinity) while preventing the premature release of drug from thedevice surface prior to device deployment at the target site.

In embodiments of the present invention, the therapeutic agent israpidly released after the medical device is brought into contact withtissue and is readily absorbed. For example, certain embodiments ofdevices of the present invention include drug coated balloon cathetersthat deliver a therapeutic agent such as a lipophilic antiproliferativepharmaceutical (such as paclitaxel or rapamycin) to nonvascular tissuethrough brief, direct pressure contact at high drug concentration duringballoon nonvascular body balloon dilation. The lipophilic drug, forexample, is retained in target tissue at the delivery site, where itinhibits hyperplasia and restenosis yet allows epithelization. In theseembodiments, coating formulations of the present invention not onlyfacilitate rapid release of drug from the balloon surface and transferof drug into target tissues during deployment, but also prevent drugfrom diffusing away from the device during transit through tortuousanatomy prior to reaching the target site and from exploding off thedevice during the initial phase of balloon inflation, before the drugcoating is pressed into direct contact with the surface of the bodylumen.

The additive according to certain embodiments has a drug affinity partand a hydrophilic part. The drug affinity part is a hydrophobic partand/or has an affinity to the therapeutic agent by hydrogen bondingand/or van der Waals interactions. The drug affinity part may includealiphatic and aromatic organic hydrocarbon compounds, such as benzene,toluene, and alkanes, among others. These parts are not water soluble.They may bind both hydrophobic drug, with which they share structuralsimilarities, and lipids of cell membranes. The drug affinity part mayinclude functional groups that can form hydrogen bonds with drug andwith itself. The hydrophilic part may include hydroxyl groups, aminegroups, amide groups, carbonyl groups, carboxylic acid and anhydrides,ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, aminoacid, amino alcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic salts and their substituted molecules,among others. One or more hydroxyl, carboxyl, acid, amide or aminegroups, for example, may be advantageous since they easily displacewater molecules that are hydrogen-bound to polar head groups and surfaceproteins of cell membranes and may function to remove this barrierbetween hydrophobic drug and cell membrane lipid. These parts candissolve in water and polar solvents. The additive of embodiments of thepresent invention has components to both bind drug and facilitate itsrapid movement off the medical device during deployment and into targettissues.

The additives in embodiments of the present invention can be surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide, or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, orester moieties are chosen from amino alcohols, hydroxyl carboxylic acidand anhydrides, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins, and theirsubstituted molecules.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties as well as non-polar hydrophobic (lipophilic)moieties.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5can be more membrane permeable. For purposes of certain embodiments ofthe present invention, for example, the additive has log P less than logP of the drug to be formulated (as an example, log P of paclitaxel is7.4). A greater log P difference between the drug and the additive canfacilitate phase separation of drug. For example, if log P of theadditive is much lower than log P of the drug, the additive mayaccelerate the release of drug in an aqueous environment from thesurface of a device to which drug might otherwise tightly adhere,thereby accelerating drug delivery to tissue during brief deployment atthe site of intervention. In certain embodiments of the presentinvention, log P of the additive is negative. In other embodiments, logP of the additive is less than log P of the drug. While a compound'soctanol-water partition coefficient P or log P is useful as ameasurement of relative hydrophilicity and hydrophobicity, it is merelya rough guide that may be useful in defining suitable additives for usein embodiments of the present invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical recipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The additives describedherein as useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants.

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of variousembodiments of the invention, as are combinations of surfactant andother additives. Surfactants often have one or more long aliphaticchains such as fatty acids that may insert directly into lipid bilayersof cell membranes to form part of the lipid structure, while othercomponents of the surfactants loosen the lipid structure and enhancedrug penetration and absorption. The contrast agent iopromide does nothave these properties.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10. In certain embodiments of thepresent invention, a higher HLB value is utilized, since increasedhydrophilicity may facilitate release of hydrophobic drug from thesurface of the device. In one embodiment, the HLB of the surfactantadditive is higher than 10. The additive HLB can be higher than 14.Alternatively, surfactants having lower HLB may be utilized to preventdrug loss prior to device deployment at the target site, for example ina top coat over a drug layer that has a very hydrophilic additive.

The HLB value of a surfactant is merely a rough guide generally used toenable formulation of industrial, pharmaceutical and cosmetic emulsions,for example. For many important surfactants, including severalpolyethoxylated surfactants, it has been reported that HLB values candiffer by as much as about 8 HLB units, depending upon the empiricalmethod chosen to determine the HLB value (Schott, J. Pharm. Sciences,79(1), 87-88 (1990)). Keeping these inherent difficulties in mind, andusing HLB values as a guide, surfactants may be identified that havesuitable hydrophilicity or hydrophobicity for use in embodiments of thepresent invention, as described herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters.

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Examples of hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Hydrophilic surfactants include PEG-20 dilaurate, PEG-20 dioleate,PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. The HLB valuesare in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and di-esters.

Polyethylene Glycol Glycerol Fatty Acid Esters.

Hydrophilic surfactants can include PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products.

Many surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Alcohols include glycerol, propyleneglycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,hydrophilic surfactants are PEG-35 castor oil (Incrocas-35), PEG-40hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate (TAGAT™ TO),PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil (Crovol A70),PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil (Emalex C-50),PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8 caprylic/capricglycerides (Labrasol), and PEG-6 caprylic/capric glycerides (Softigen767). For example, hydrophobic surfactants in this class include PEG-5hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9hydrogenated castor oil, PEG-6 corn oil (Labrafil™ M 2125 CS), PEG-6almond oil (Labrafil™ M 1966 CS), PEG-6 apricot kernel oil (Labrafil™ M1944 CS), PEG-6 olive oil (Labrafil™ M 1980 CS), PEG-6 peanut oil(Labrafil™ M 1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil™ M2130 BS), PEG-6 palm kernel oil (Labrafil™ M 2130 CS), PEG-6 triolein(Labrafil™b M 2735 CS), PEG-8 corn oil (Labrafil™ WL 2609 BS), PEG-20corn glycerides (Crovol M40), and PEG-20 almond glycerides (Crovol A40).

Polyglyceryl Fatty Acids.

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, hydrophobic surfactants include polyglyceryl oleate (PlurolOleique), polyglyceryl-2 dioleate (Nikkol DGDO), polyglyceryl-10trioleate, polyglyceryl stearate, polyglyceryl laurate, polyglycerylmyristate, polyglyceryl palmitate, and polyglyceryl linoleate.Hydrophilic surfactants include polyglyceryl-10 laurate (Nikkol Decaglyn1-L), polyglyceryl-10 oleate (Nikkol Decaglyn 1-O), and polyglyceryl-10mono, dioleate (CaproI™ PEG 860), polyglyceryl-10 stearate,polyglyceryl-10 laurate, polyglyceryl-10 myristate, polyglyceryl-10palmitate, polyglyceryl-10 linoleate, polyglyceryl-6 stearate,polyglyceryl-6 laurate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, and polyglyceryl-6 linoleate. Polyglyceryl polyricinoleates(Polymuls) are also surfactants.

Propylene Glycol Fatty Acid Esters.

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-06), propylene glycol dicaprylate/dicaprate(Captex™ 200), and propylene glycol dioctanoate (Captex™ 800).

Sterol and Sterol Derivatives.

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Derivatives include thepolyethylene glycol derivatives. A surfactant in this class is PEG-24cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters.

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, surfactants include PEG-20sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60). PEG-20 sorbitanmonooleate (Tween-80). In some embodiments, laurate esters are utilizedbecause they have a short lipid chain compared with oleate esters,increasing drug absorption.

Polyethylene Glycol Alkyl Ethers.

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Ethersinclude PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij 30).

Sugar and its Derivatives.

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols.

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,octoxynol-9, nonoxynol, and are suitable for use in embodiments of thepresent invention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers.

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic™ series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote the numberof polyoxyethylene and polyoxypropylene units, respectively.

Hydrophilic surfactants of this class include Poloxamers 108, 188, 217,238, 288, 338, and 407. Hydrophobic surfactants in this class includePoloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters.

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, hydrophobicsurfactants include sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), and sorbitan monooleate (Span-80), sorbitanmonostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). Second, when the pH increases so as toconvert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants.

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Ionic surfactants include quaternary ammoniumsalts, fatty acid salts and bile salts. Specifically, ionic surfactantsinclude benzalkonium chloride, benzethonium chloride, cetylpyridiniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphenbromide, dialkylester of sodium sulfonsuccinic acid, sodium dioctylsulfosuccinate, sodium cholate, and sodium taurocholate. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Some of the surfactants described herein are very stable under heating.They survive an ethylene oxide sterilization process. They do not reactwith drugs such as paclitaxel or rapamycin under the sterilizationprocess. The hydroxyl, ester, amide groups are utilized because they areunlikely to react with drug, while amine and acid groups often do reactwith paclitaxel or rapamycin during sterilization. Furthermore,surfactant additives improve the integrity and quality of the coatinglayer, so that particles do not fall off during handling. When thesurfactants described herein are formulated with paclitaxel,experimentally it protects drug from premature release during the devicedelivery process while facilitating rapid release and elution ofpaclitaxel during a very brief deployment time of 0.2 to 10 minutes atthe target site. Drug absorption by tissues at the target site isunexpectedly high experimentally.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid, Amide, or Ester Moieties.

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide, or ester moieties include creatine, creatinine,agmatine, citrulline, guanidine, sucralose, aspartame, hypoxanthine,theobromine, theophylline, adenine, uracil, uridine, guanine, thymine,thymidine, xanthine, xanthosine, xanthosine monophosphate, caffeine,allantoin, (2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea,pentaerythritol ethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, N-acetylglucosamine,N-octyl-D-gluconamide, C6-ceramide, dihydro-C6-ceramide, cerabroside,sphingomyelin, galaclocerebrosides, lactocerebrosides,N-acetyl-D-sphingosine, N-hexanoyl-D-sphingosine,N-octonoyl-D-sphingosine, N-Lauroyl-D-sphingosine,N-palmitoyl-D-sphingosine, N-oleoyl-D-sphingosine, PEG caprylic/capricdiglycerides, PEG8 caprylic/capric glycerides, PEG caprylate, PEG8caprylate (e.g., Labrasol®), PEG caprate, PEG caproate, glycerylmonocaprylate, glyceryl monocaprate, glyceryl monocaproate, monolaurin,monocaprin, monocaprylin, monomyristin, monopalmitolein, and monoolein.

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide, or ester moieties include amino alcohols,hydroxyl carboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohols and organic acids, and theirsubstituted molecules. Hydrophilic chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moietieshaving a molecular weight less than 5,000-10,000 are utilized in certainembodiments. In other embodiments, molecular weight of the additive withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estermoieties is less than 1000-5,000, or less than 750-1,000, or less than750. In these embodiments, the molecular weight of the additive is to beless than that of the drug to be delivered. Further, the molecularweight of the additive is to be higher than 80 since molecules withmolecular weight less than 80 very easily evaporate and do not stay inthe coating of a medical device. Small molecules can diffuse quickly.They can release themselves easily from the delivery balloon,accelerating release of drug, and they can diffuse away from drug whenthe drug binds tissue of the body lumens.

In certain embodiments, additives with more than four hydroxyl groupsare utilized, for example in the case of a high molecular weightadditive. Large molecules diffuse slowly. If the molecular weight of theadditive or the chemical compound is high, for example if the molecularweight is above 800, above 1000, above 1200, above 1500, or above 2000;large molecules may elute off the surface of the medical device tooslowly to release drug under 2 minutes. If these large molecules containmore than four hydroxyl groups they have increased hydrophilicproperties, which is necessary for relatively large molecules to releasedrug quickly. The increased hydrophilicity helps elute the coating offthe balloon, accelerates release of drug, and improves or facilitatesdrug movement through water barrier and polar head groups of lipidbilayers to penetrate tissues. In one embodiment, the hydroxyl group isutilized as the hydrophilic moiety because it is unlikely to react withwater insoluble drug, such as paclitaxel or rapamycin. In someembodiments, the chemical compound having more than four hydroxyl groupshas a melting point of 120° C. or less. In some embodiments, thechemical compound having more than four hydroxyl groups has threeadjacent hydroxyl groups that in stereo configuration are all on oneside of the molecule. For example, sorbitol and xylitol have threeadjacent hydroxyl groups that in stereo configuration are all on oneside of the molecule, while galactitol does not. The difference impactsthe physical properties of the isomers such as the melting temperature.The stereo configuration of the three adjacent hydroxyl groups mayenhance drug binding. This will lead to improved compatibility of thewater insoluble drug and hydrophilic additive, and improved tissueuptake and absorption of drug.

Some of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described herein are very stableunder heating. They survive an ethylene oxide sterilization process anddo not react with the water insoluble drug paclitaxel or rapamycinduring sterilization. L-ascorbic acid and its salt and diethanolamine,on the other hand, do not necessarily survive such a sterilizationprocess, and they react with paclitaxel. A different sterilizationmethod is therefore utilized for L-ascorbic acid and diethanolamine. Forexample, hydroxyl, ester, and amide groups are utilized because they areunlikely to react with therapeutic agents such as paclitaxel orrapamycin. Sometimes, amine and acid groups do react with paclitaxel,for example, experimentally, benzoic acid, gentisic acid,diethanolamine, and ascorbic acid were not stable under ethylene oxidesterilization, heating, and aging process and reacted with paclitaxel.When the chemical compounds described herein are formulated withpaclitaxel, a top coat layer may be advantageous to prevent prematuredrug loss during the device delivery process before deployment at thetarget site, since hydrophilic small molecules sometimes release drugtoo easily. The chemical compounds herein rapidly elute drug off theballoon during deployment at the target site. Surprisingly, even thoughsome drug is lost during transit of the device to the target site whenthe coating contains these additives, experimentally drug absorption bytissue is unexpectedly high after only 0.2-10 minutes of deployment, forexample, with the additive hydroxyl lactones such as ribonic acidlactone and gluconolactone.

Fat-Soluble Vitamins and Salts Thereof.

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to theseseveral other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and their Amphiphilic Derivatives.

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfate, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and their Salts.

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has solubilityin unbuffered water of less than about 4% (40 mg/ml). These includecystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins.

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a useful additive since it iswater-soluble and contains significant hydrophobic parts to bind drug:paclitaxel is 89% to 98% protein-bound after human intravenous infusion,and rapamycin is 92% protein bound, primarily (97%) to albumin.Furthermore, paclitaxel solubility in PBS increases over 20-fold withthe addition of BSA. Albumin is naturally present at high concentrationsin serum and is thus very safe for human use.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and their Esters and Anhydrides.

Examples include acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the walls of the body lumen.

Other Chemical Compounds with One or More Hydroxyl, Amine, Carbonyl,Carboxyl, or Ester Moieties.

The additives according to embodiments include amino alcohols, alcohols,amines, acids, amides, and hydroxyl acids in both cyclo and linearaliphatic and aromatic groups. Examples are L-ascorbic acid and itssalt, D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphate,sugar sulphates, sinapic acid, vanillic acid, vanillic aciddiethylamide, vanillin, methyl paraben, propyl paraben, xylitol,2-ethoxyethanol, sugars, galactose, glucose, ribose, mannose, xylose,sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described herein, polyglycidol, glycerol, multiglycerols(e.g., chemical compounds with multiple hydroxyl, amino, carbonyl,carboxyl, or ester moieties), galactitol, di(ethylene glycol),tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol),poly(ethylene glycol) oligomers, di(propylene glycol), tri(propyleneglycol), tetra(propylene glycol, and penta(propylene glycol),poly(propylene glycol) oligomers, a block copolymer of polyethyleneglycol and polypropylene glycol, and derivatives and combinationsthereof.

Combinations of additives can also be useful for purposes of the presentinvention. One embodiment includes the combination or mixture of twoadditives, for example, a first additive including a surfactant and asecond additive including a chemical compound with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties.

The combination or mixture of the surfactant and the small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationsincluding mixtures of the two additives with water-insoluble drug are incertain cases superior to mixtures including either additive alone. Thehydrophobic drugs bind extremely water-soluble small molecules morepoorly than they do surfactants. They are often phase separated from thesmall water-soluble molecules, which can lead to suboptimal coatinguniformity and integrity. The water-insoluble drug has Log P higher thanboth that of the surfactant and that of small water-soluble molecules.However, Log P of the surfactant is typically higher than Log P of thechemical compounds with one or more hydroxyl, amine, carbonyl, carboxyl,or ester moieties. The surfactant has a relatively high Log P (usuallyabove 0) and the water-soluble molecules have low Log P (e.g., below 0).Some surfactants, when used as additives in embodiments of the presentinvention, adhere so strongly to the water-insoluble drug and thesurface of the medical device that drug is not able to rapidly releasefrom the surface of the medical device at the target site. On the otherhand, some of the water-soluble small molecules (with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere so poorlyto the medical device that they release drug before it reaches thetarget site, for example, into serum during the transit of a coatedballoon catheter to the site targeted for intervention. Surprisingly, byadjusting the ratio of the concentrations of the small hydrophilicmolecule and the surfactant in the formulation, the inventor has foundthat the coating stability during transit and rapid drug release wheninflated and pressed against tissues of the lumen wall at the targetsite of therapeutic intervention in certain cases is superior to aformulation including either additive alone. Furthermore, the presenceof the surfactant improves the miscibility and compatibility of thewater-insoluble drug and the highly water-soluble molecules. Thesurfactant also improves coating uniformity and integrity by its goodadhesion to the drug and the small molecules. The long chain hydrophobicpart of the surfactant binds drug tightly while the hydrophilic part ofthe surfactant binds the water-soluble small molecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture may be chosen from PEG sorbitan fattyesters; PEG omega-3 fatty esters, ethers, and alcohols; glycerol fattyesters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG fattyesters and alcohols, sugar fatty esters, PEG sugar esters, Tween 20,Tween 40, Tween 60, p-isononylphenoxypolyglycidol, PEG laurate, PEGoleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEGglyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, Tween 20, Tween40, Tween 60, Tween 80, octoxynol, octoxynol-9, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside and their derivatives.

Embodiments of the chemical compound with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties in the mixture or the combinationcan include any of the chemical compounds with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties described herein for use inembodiments of the invention. In various embodiments, the chemicalcompound with one or more hydroxyl, amine, carbonyl, carboxyl, or estermoieties in the mixture has at least one hydroxyl group. In certainembodiments, additives with more than four hydroxyl groups are utilized,for example in the case of a high molecular weight additive. In someembodiments, the chemical compound having more than four hydroxyl groupshas a melting point of 120° C. or less. Large molecules diffuse slowly.If the molecular weight of the additive or the chemical compound ishigh, for example if the molecular weight is above 800, above 1000,above 1200, above 1500, or above 2000; large molecules may elute off thesurface of the medical device too slowly to release drug under 2minutes. If these large molecules contain more than four hydroxyl groupsthey have increased hydrophilic properties, which is necessary forrelatively large molecules to release drug quickly. The increasedhydrophilicity helps elute the coating off the balloon, acceleratesrelease of drug, and improves or facilitates drug movement through waterbarrier and polar head groups of lipid bilayers to penetrate tissues. Inone embodiment, the hydroxyl group is utilized as the hydrophilic moietybecause it is unlikely to react with water insoluble drug, such aspaclitaxel or rapamycin.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture is chosen from L-ascorbicacid and its salt, D-glucoascorbic acid and its salt, tromethamine,triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone, lactobionic acid,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate salt, gentisic acid,lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates,glucopyranose phosphate, sugar sulphates, sinapic acid, vanillic acid,vanillin, methyl paraben, propyl paraben, xylitol, 2-ethoxyethanol,sugars, galactose, glucose, ribose, mannose, xylose, sucrose, lactose,maltose, arabinose, lyxose, fructose, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described herein, polyglycidol, glycerol, multiglycerols,galactitol, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, di(ethylene glycol),tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol),poly(ethylene glycol) oligomers, di(propylene glycol), tri(propyleneglycol), tetra(propylene glycol, and penta(propylene glycol),poly(propylene glycol) oligomers, a block copolymer of polyethyleneglycol and polypropylene glycol, and derivatives and combinationsthereof.

Mixtures or combinations of a surfactant and a water-soluble smallmolecule confer the advantages of both additives. The water insolubledrug often has a poor compatibility with highly water-soluble chemicalcompounds, and the surfactant improves compatibility. The surfactantalso improves the coating quality, uniformity, and integrity, andparticles do not fall off the balloon during handling. The surfactantreduces drug loss during transit to a target site. The water-solublechemical compound improves the release of drug off the balloon andabsorption of the drug in the tissue. Experimentally, the combinationwas surprisingly effective at preventing drug release during transit andachieving high drug levels in tissue after very brief 0.2 to 2 minutedeployment. Furthermore, in animal studies it effectively reducedstenosis and late lumen loss.

Some of the mixtures or combinations of surfactants and water-solublesmall molecules are very stable under heating. They survived an ethyleneoxide sterilization process and do not react with the water insolubledrug paclitaxel or rapamycin during sterilization. In one embodiment,the hydroxyl, ester, amide groups are utilized because they are unlikelyto react with therapeutic agents such as paclitaxel or rapamycin.Sometimes amine and acid groups do react with paclitaxel and are notstable under ethylene oxide sterilization, heating, and aging. When themixtures or combinations described herein are formulated withpaclitaxel, a top coat layer may be advantageous in order to protect thedrug layer and from premature drug loss during the device.

Examples of additives include p-isononylphenoxypolyglycidol, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, octoxynol, octoxynol-9, monoxynol, tyloxapol,sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids), cetotiamine, cyclothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, monolaurin, monocaprin,monocaprylin, monomyristin, monopalmitolein, monoolein, creatine,creatinine, agmatine, citrulline, guanidine, sucralose, aspartame,hypoxanthine, theobromine, theophylline, adenine, uracil, uridine,guanine, thymine, thymidine, xanthine, xanthosine, xanthosinemonophosphate, caffeine, allantoin, (2-hydroxyethyl)urea,N,N′-bis(hydroxymethyl)urea, pentaerythritol ethoxylate, pentaerythritolpropoxylate, pentaerythritol propoxylate/ethoxylate, glycerolethoxylate, glycerol propoxylate, trimethylolpropane ethoxylate,pentaerythritol, dipentaerythritol, crown ether, 18-crown-6, 15-crown-5,12-crown-4, di(ethylene glycol), tri(ethylene glycol), tetra(ethyleneglycol), penta(ethylene glycol), poly(ethylene glycol) oligomers,di(propylene glycol), tri(propylene glycol), tetra(propylene glycol, andpenta(propylene glycol), poly(propylene glycol) oligomers, a blockcopolymer of polyethylene glycol and polypropylene glycol, andderivatives and combinations thereof. (chemical compounds with one ormore hydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some ofthese additives are both water-soluble and organic solvent-soluble. Theyhave good adhesive properties and adhere to the surface of polyamidemedical devices, such as balloon catheters. They may therefore be usedin the adherent layer, top layer, and/or in the drug layer ofembodiments of the present invention. The aromatic and aliphatic groupsincrease the solubility of water insoluble drugs in the coatingsolution, and the polar groups of alcohols and acids accelerate drugpermeation of tissue.

Other additives according to embodiments of the invention includehydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxyl ester, andhydroxyl amide. Examples are gluconolactone, D-glucoheptono-1,4-lactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, erythronicacid lactone, ribonic acid lactone, glucuronic acid, gluconic acid,gentisic acid, lactobionic acid, lactic acid, acetaminophen, vanillicacid, sinapic acid, hydroxybenzoic acid, methyl paraben, propyl paraben,and derivatives thereof.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may form hydrogen bonds and/or van der Waalsinteractions with drug. They are also useful in the top layer in thecoating. Compounds containing one or more hydroxyl, carboxyl, or aminegroups, for example, are especially useful as additives since theyfacilitate drug release from the device surface and easily displacewater next to the polar head groups and surface proteins of cellmembranes and may thereby remove this barrier to hydrophobic drugpermeability. They accelerate movement of a hydrophobic drug off theballoon to the lipid layer of cell membranes and tissues for which ithas very high affinity. They may also carry or accelerate the movementof drug off the balloon into more aqueous environments such as theinterstitial space, for example, of nonvascular tissues that have beeninjured by balloon angioplasty or stent expansion. Additives such aspolyglyceryl fatty esters, ascorbic ester of fatty acids, sugar esters,alcohols and ethers of fatty acids have fatty chains that can integrateinto the lipid structure of target tissue membranes, carrying drug tolipid structures. Some of the amino acids, vitamins and organic acidshave aromatic C═N groups as well as amino, hydroxyl, and carboxyliccomponents to their structure. They have structural parts that can bindor complex with hydrophobic drug, such as paclitaxel or rapamycin, andthey also have structural parts that facilitate tissue penetration byremoving barriers between hydrophobic drug and lipid structure of cellmembranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for walls of the body lumen and candisplace hydrogen-bound water molecules. At the same time, they havelong chains of fatty acid, alcohol, ether, and ester that can bothcomplex with hydrophobic drug and integrate into the lipid structure ofthe cell membranes to form the part of the lipid structure. Thisdeformation or loosening of the lipid membrane of target cells mayfurther accelerate permeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They also have structural components including aromatic C═N, amino,hydroxyl, and carboxylic groups. These structures have very goodcompatibility with paclitaxel and rapamycin and can increase thesolubility of these water-insoluble drugs in water and enhance theirabsorption into tissues. However, they often have poor adhesion to thesurface of medical devices. They are therefore used in combination withother additives in the drug layer and top layer where they are useful toenhance drug absorption. Vitamin D2 and D3 are especially useful becausethey themselves have anti-restenotic effects and reduce thrombosis,especially when used in combination with paclitaxel.

In embodiments of the present invention, the additive is soluble inaqueous solvents and is soluble in organic solvents. Extremelyhydrophobic compounds that lack sufficient hydrophilic parts and areinsoluble in aqueous solvent, such as the dye Sudan Red, are not usefulas additives in these embodiments. Sudan red is also genotoxic.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or from about 2 to 6 μg/mm², or about 0.5microgram/mm² or less, or less than, equal to, or greater than about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20 micrograms/mm²or more. If the medical device is a balloon, these measurements arecalculated at nominal diameter. In one embodiment, the concentration ofthe at least one additive applied to the surface of the medical deviceis from about 0.5 to 20 μg/mm², or from about 2 to 6 μg/mm², or about0.5 microgram/mm² or less, or less than, equal to, or greater than about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or about 20micrograms/mm² or more. The ratio of additives to drug by weight in thecoating layer in embodiments of the present invention can be about 20 to0.05, about 10 to 0.1, or about 5 to 0.15.

The relative amount of the therapeutic agent and the additive in thecoating layer, may vary depending on applicable circumstances. Theoptimal amount of the additive can depend upon, for example, theparticular therapeutic agent and additive selected, the critical micelleconcentration of the surface modifier if it forms micelles, thehydrophilic-lipophilic-balance (HLB) of a surfactant or an additive'soctonol-water partition coefficient (P), the melting point of theadditive, the water solubility of the additive and/or therapeutic agent,the surface tension of water solutions of the surface modifier, and thelike.

Other considerations will further inform the choice of specificproportions of different additives. These considerations can include thedegree of bioacceptability of the additives and the desired dosage oftherapeutic agent to be provided.

Therapeutic Agent.

The therapeutic agent which can be used in embodiments of the presentinvention, can be any drugs or biologically active materials. Thetherapeutic agent can be a hydrophobic therapeutic agent, anantiproliferative therapeutic agent, an anti-inflammatory agent, or acombination thereof. The drugs can be of various physical states, e.g.,molecular distribution, crystal forms or cluster forms. Examples ofdrugs that are especially useful in embodiments of the present inventionare lipophilic substantially water insoluble drugs, such as paclitaxel,rapamycin, daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 andanalogues and derivatives thereof. These drugs are especially suitablefor use in a coating on a balloon catheter used to treat tissue of thevasculature. Therapeutic agents, such as antiproliferative drugs, suchas paclitaxel, taxol, docetaxel, rapamycin, sirolimus, tacrolimus,everolimus, mTOR inhibitors (i.e., a class of drugs that inhibit themechanistic target of rapamycin), or their analogues, can be deliveredto the wall of a body lumen to treat the narrowing or stricture.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, antiproliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, anti-inflammatory agents, and combinations thereof.

Some drugs that can be useful in various embodiments, such asparticularly for the airway, sinus, and other nasal lumens but also forurethral applications are corticosteroids such as, budesonide,flunisolide, triamcinolone, beclomethasone, fluticasone, mometasone,mometasone furoate, dexamethasone, hydrocortisone, methylprednisolone,prednisone, cotisone, betamethasone, triamcinolone acetonide, or thelike. Some other suitable drugs are terbutaline, albuterol, ipratropium,pirbuterol, epinephrine, salmeterol, levalbuterol, formoterol, or thelike; the drug can be a bronchodilator or a vasoconstrictor.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Antiproliferative agents can include drugs such asamlodipine and doxazosin. Anti-mitotic agents and anti-metabolite agentsthat can be used in embodiments of the present invention include drugssuch as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-anti sense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, β-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferonα, β- and γ, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or BcI-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneiA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Solvents.

Solvents for preparing of the coating layer may include, as examples,one or combination of the following: (a) water, (b) alkanes such ashexane, octane, cyclohexane, and heptane, (c) aromatic solvents such asbenzene, toluene, and xylene, (d) alcohols such as ethanol, propanol,and isopropanol, diethylamide, ethylene glycol monoethyl ether,Trascutol, and benzyl alcohol (e) ethers such as dioxane, dimethyl etherand tetrahydrofuran, (f) esters/acetates such as ethyl acetate andisobutyl acetate, (g) ketones such as acetone, acetonitrile, diethylketone, and methyl ethyl ketone, and (h) mixture of water and organicsolvents such as water/ethanol, water/acetone, water/methanol,water/tetrahydrofuran. A solvent in the top coating layer can be, forexample, methanol, ethanol, and acetone.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful solvents in embodiments of the presentinvention because these organic solvents generally disrupt colloidalaggregates and co-solubilize all the components in the coating solution.

The therapeutic agent and additive or additives may be dispersed in,solubilized, or otherwise mixed in the solvent. The weight percent ofdrug and additives in the solvent may be in the range of 0.1-80% byweight, or 2-20% by weight.

Various embodiments provide a method for preparing a balloon catheter.First, a coating solution or suspension including at least one solvent,at least one therapeutic agent, and at least one additive is prepared.In at least one embodiment, the coating solution or suspension includesonly these three components. The content of the therapeutic agent in thecoating solution can be from 0.5-50% by weight based on the total weightof the solution. The content of the additive in the coating solution canbe from about 0.1 wt % to about 45 wt %, about 0.2 wt % to about 40 wt %by weight, about 0.3 to about 15 wt %, or about 0.1 wt % or less, orless than, equal to, or greater than about 0.2 wt %, 0.3, 0.4, 0.5, 0.6,0.8, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28,30, 35, 40, or about 45 wt % or more, based on the total weight of thesolution. The amount of solvent used depends on the coating process andviscosity. It will affect the uniformity of the drug-additive coatingbut will be evaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more additives may be used in the coatingsolution.

In other embodiments, a therapeutic agent, an additive and a polymericmaterial may be used in the coating solution for the balloon catheter.In the coating, the therapeutic agent is not encapsulated in polymerparticles.

Various techniques may be used for applying a coating solution to amedical device such as casting, fixed volume liquid dispensing, metering(e.g., dispense a fixed amount of coating solution based on volume ontothe balloon), spinning, spraying, dipping (immersing), ink jet printing,electrostatic techniques, and combinations of these processes. Duringthe application of the coating solution, the balloon can be at leastpartially inflated. The metering can be performed in any suitable way,such as by pumping liquid coating solution from a reservoir to a nozzlethat is proximate the surface of the balloon (e.g., the surface of an atleast partially inflated balloon). The nozzle can dispense the liquidtherefrom, which can be immediately transferred to the exterior of theballoon due to its proximity to the nozzle (e.g., the nozzle can be soclose to the balloon that the liquid emerging from the nozzle cancontact and be transferred to the exterior of the balloon before forminga drop of liquid that leaves the nozzle). The nozzle can dispense theliquid to the exterior of the balloon such that substantially none ofthe liquid is lost. The balloon can be rotated around its longitudinalaxis during the dispensing of the liquid from the nozzle. The nozzle canmove during the dispensing, such as along the exterior of the balloonparallel to the longitudinal axis of the balloon. In some embodiments,the balloon can be rotated around its longitudinal axis during thedispensing, and the nozzle can move parallel to the longitudinal axis ofthe balloon, such that substantially all of the balloon surface iscoated with the coating solution (e.g., similar to the movement of awoodworker's chisel on a cylindrical piece of spinning wood in a lathe).

Choosing an application technique principally depends on the viscosityand surface tension of the solution. In some embodiments of the presentinvention, metering can be utilized because it makes it easier tocontrol the uniformity of the thickness of the coating layer as well asthe concentration of the therapeutic agent applied to the medicaldevice.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon by metering it on while the balloon is inflated and rotatingalong its longitudinal axis. The balloon is then allowed to dry beforebeing deflated, folded, and sheathed.

The description of an embodiment of an application device, fixture, andmetering technique is an example. Any suitable metering or othertechnique may be used for coating the balloon catheter.

After the medical device is coated with the coating solution, the coatedballoon is subjected to a drying in which the solvent in the coatingsolution is evaporated. This produces a coating matrix on the ballooncontaining the therapeutic agent. One example of a drying technique isplacing a coated balloon into an oven at approximately 20° C. or higherfor approximately 24 hours. Any other suitable method of drying thecoating solution may be used. The time, temperature, and relativehumidity may vary with particular additives and therapeutic agents.

An embodiment of the present invention relates to a method of treating abenign prostatic hyperplasia. The method includes inserting a medicaldevice including a coating into a prostatic urethra. The coating layerincludes a therapeutic agent and an additive. In this embodiment, themedical device can be configured as having at least an expandableportion. Some examples of such devices include balloon catheters, fixedwire balloon catheter, over the wire balloon catheter, rapid exchangecatheter, perfusion balloon catheters, an infusion catheter (e.g.,distal perforated drug infusion catheters, a perforated balloon, spaceddouble balloon, porous balloon, and weeping balloon, cutting ballooncatheters), spaced double balloons, cutting balloon catheter, scoringballoon catheters, self-expanded and balloon expanded-stents, guidecatheters, guide wires, embolic protection devices, and various imagingdevices.

As mentioned herein, one example of a medical device that isparticularly useful in the present invention is a coated ballooncatheter. A balloon catheter typically has a long, narrow, hollow tubetabbed with a miniature, deflated balloon. In embodiments of the presentinvention, the balloon is coated with a drug solution. Then, the balloonis maneuvered through the stricture in the nonvascular body lumen to thesite of a blockage, occlusion, or other tissue requiring a therapeuticagent. Once in the proper position, the balloon is inflated and contactsthe walls of the stricture in the nonvascular body lumen and/or ablockage or occlusion. It is an object of embodiments of the presentinvention to rapidly deliver drug to and facilitate absorption by targettissue. In various embodiments, it can be advantageous to efficientlydeliver drug to tissue in as brief a period as possible while the deviceis deployed at the target site. The therapeutic agent can be releasedinto such tissue, for example the lumen walls, in about 0.1 to 30minutes, for example, or about 0.1 to 10 minutes, or about 0.2 to 2minutes, or about 0.1 to 1 minutes, of balloon inflation time pressingthe drug coating into contact with diseased nonvascular tissue.

Given that a therapeutically effective amount of the drug can bedelivered by embodiments of the present invention into, for example, theprostate, in some cases the need for a stent may be eliminated,obviating the complications of fracture and dripping associatedtherewith.

The balloon catheter may be used to treat nonvascular tissue/diseasealone or in combination with other methods and medical devices fortreating the non-vasculature, for example, direct vision internalurethrotomy (DVIU) for strictures and transurethral resection of theprostate (TURP) for BPH. DVIU is a procedure used to open a urethralstricture. Specifically, DVIU is a procedure in which relaxing incisionsare made in a stricture to create urethral luminal gain. DVIU may beaccomplished using cold knife (urethrotome) or a hot knife (electrode).The cutter is inserted into the body and advanced through the urethra tothe area of narrowing. After the relaxing incisions have been made,balloon dilation using the coated balloon of embodiments of the presentinvention may be performed. In addition, stenting may be performedthereafter, or simultaneous with expansion of the coated balloon asdescribed herein. In another embodiment, balloon dilation using thecoated balloon of embodiments of the present invention may be performedinside a placed stent. For TURP the medical device typically used is ahot knife (electrode) or a laser. In either case the device is insertedinto the body and advanced through the urethra to the area of narrowing.After the prostatic tissue has been excised, balloon dilation using thecoated balloon of embodiments of the present invention may be performed.In addition, stenting may be performed thereafter, or simultaneous withexpansion of the coated balloon as described herein. In anotherembodiment a self-expanding stent coated with the therapeutic agents andadditives of the present invention may be delivered and placed insidethe body lumen strictures including esophageal strictures, achalasiastrictures, biliary strictures, stomach strictures, small intestinestrictures, duodenum strictures, jejunum strictures, ileum strictures,colon strictures, rectum strictures, and large intestine strictures.

Preparation.

Various embodiments of the present invention provide a method of forminga balloon. The method can include placing a tube including balloonmaterial into a balloon mold having any suitable shape, such as aballoon mold having a shape including a proximal cone, at least one mainbody section, at least one neck section having a diameter less than theat least one main body section, another at least one main body section,and a distal cone. The method can include pressurizing the interior ofthe balloon material tube. The method can also include expanding theballoon material tube into contact with the interior of the mold.

Various embodiments of the present invention provide a method of forminga balloon and then shrinking it to get a large diameter range. Themethod includes placing a tube including balloon material into a balloonmold wherein the balloon mold has a shape including a proximal cone, atleast one main body section, and a distal cone. The method includespressurizing the interior of the balloon material tube. The methodincludes expanding the balloon material tube into contact with theinterior of the mold at pressures of 200-400 psi and temperatures of100-200° C. The formed balloon is then shrunk by annealing the balloonat a temperature lower than the forming process with low inflationpressure for a specified amount of time, preferably 1-30 psi at 70-90°C., for 3-30 seconds. Once the balloon is shrunk it can be attached to acatheter shaft and coated with drug. Any of the manufacturingtechniques, methods of treating body lumens, or balloons described inthe following patents, which are hereby incorporated by reference as ifthey were reproduced herein in their entirety, can be used inembodiments of the present invention: U.S. Pat. Nos. 7,163,522 and7,108,826.

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, anadditive, and a solvent, simultaneously together. Also, the coatingsolution can be prepared by sequentially adding each component based onsolubility or any other parameters. For example, the coating solutioncan be prepared by first adding the therapeutic agent to the solvent andthen adding the additive. Alternatively, the additive can be added tothe solvent first and then the therapeutic agent can be later added. Ifthe solvent used does not sufficiently dissolve the drug, it is usefulto first add the additive to the solvent, then the drug, since theadditive will increase drug solubility in the solvent.

International Prostate Symptom Score (IPSS) and Q_(max).

Q_(max) is a measure of the maximum urine flow rate obtained during aurodynamics test. It is the maximum volumetric flow rate of urine duringurination. It is a measure of the quantity of urine voided in aspecified period of time (per second or per minute). It may be measuredwith uroflowmetry. Q_(max) indicates the maximum flow rate. Q_(max) isused as an indicator for the diagnosis of enlarged prostate or otherurinary tract occlusion or stricture. A lower Q_(max) may indicate thatthe enlarged prostate puts pressure on the urethra or that the urethralstricture has partially occluded the urethra.

By using this invention, for example, the balloon shown in FIG. 3 , apatient with urethral strictures can experience an increase in Q_(max).The typical Q_(max) for a person with a urethral stricture is in therange of 0 to 10 mL/s. Following treatment (measurements usually takenbetween 14 and 30 days following treatment) with the balloon of thisinvention, the Q_(max) would be expected to increase to 9 to 52 mL/s, ora minimum of 15 mL/s or, in some embodiments, to a minimum of 20 mL/sor, in some embodiments, to less than, equal to, or greater than about 8mL/s, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30,35, 40, 45, or about 50 mL/s or more. This treatment has been shown tohave a long-term effect on Q_(max). In some embodiments, after 6 months,Q_(max) can still be at or above 15 mL/s, 20 mL/s, or in the range of 6to 50 mL/s, or less than, equal to, or greater than about 8 mL/s, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 45,or about 50 mL/s or more. After 12 months, in various embodiments,Q_(max) can still be above 15 mL/s, 20 mL/s, or in the range of 6 to 50mL/s, 9 to 32 mL/s, or less than, equal to, or greater than about 8mL/s, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30,35, 40, 45, or about 50 mL/s or more.

By using this invention, for example, the balloon shown in FIG. 1A,1B,1C, or 2, a patient with benign prostate hyperplasia can experience anincrease in Q_(max). The typical Q_(max) for a person with a BPH is inthe range of 5 to 12 mL/s. Following treatment with the balloon of thisinvention, in various embodiments, the Q_(max) can increase to a minimumof 16 mL/s, to a range of 4 to 35 mL/s, or less than, equal to, orgreater than about 8 mL/s, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 22, 24, 26, 28, 30, 35, 40, 45, or about 50 mL/s or more. Thetreatment has been shown to have a long-term effect on Q_(max). After 6months, Q_(max) can be above a minimum of 16 mL/s or, in someembodiments, in the range of 16 to 32 mL/s, or less than, equal to, orgreater than about 8 mL/s, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 22, 24, 26, 28, 30, 35, 40, 45, or about 50 mL/s or more. After 12months, Q_(max) can be above a minimum of 16 mL/s or, in someembodiments, in the range of 16 to 30 mL/s, or less than, equal to, orgreater than about 8 mL/s, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 22, 24, 26, 28, 30, 35, 40, 45, or about 50 mL/s or more. Theseeffects distinguish the current invention from prior art devices andmethods.

The International Prostate Symptom Score (IPSS) is a validatedpatient-reported outcome measures (PROM) scoring system. Urologistsaccept it worldwide and it is used to screen for and diagnose benignprostatic hyperplasia (BPH) as well as to monitor symptoms and guidedecisions about how to manage the disease. The IPSS is based on theanswers to eight questions, seven regarding disease symptoms and onequestion related to the patient's quality of life. For the symptomquestions, the patient is asked to choose the rating that bestrepresents their condition. The scale ranges from 0 to 5, with 5representing the most symptomatic disease. The seven symptom scores aresummed to give an overall maximum possible score of 35. The answer tothe quality of life question is scored on a scale of 0 to 6. Accordingto these scoring systems, the scores can be categorized as follows:symptoms are mild if the score is 7 or less; symptoms are moderate ifthe score is 8 to 19; and symptoms are severe if the score is 20 to 35.

By using this invention, for example the balloon shown in FIG. 3 , apatient with urethral strictures can experience a decrease in IPSS. Thetypical IPSS for a person with a urethral stricture is in the range of15 to 35. Following treatment with the balloon of this invention, theIPSS would be expected to be at a maximum of 14 or, in some embodimentsbe in the range of 0 to 13, 4 to 13, 0 to 11, or 0, or less than, equalto, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, orabout 14. This treatment has been shown to have a long-term effect onIPSS. After 6 months, IPSS is still below a maximum of 14 and in someembodiments in the range of 0 to 13, 1 to 13, 0 to 11, or 0, or lessthan, equal to, or greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, or about 14. After 12 months, IPSS is still below a maximum of14, or can be 0 to 7, or 0, or less than, equal to, or greater thanabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. Theseeffects distinguish the current invention from prior art devices andmethods.

By using this invention, for example the balloon catheter shown in FIG.1A,1B, 1C, or 2, a patient with benign prostate hyperplasia canexperience a decrease in IPSS. The typical IPSS for a person with a BPHis in the range of 15 to 35. Following treatment with the balloon ofthis invention, the IPSS can be at a maximum of 14 or, in someembodiments, in the range of 4 to 13, or 0, or less than, equal to, orgreater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about14. This treatment can have a long-term effect on IPSS. After 6 months,IPSS can still be at a maximum of 14 and in some embodiments in therange of 1 to 13, or 0, or less than, equal to, or greater than about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. After 12 months,IPSS can still be under a maximum of 14 or in some embodiments in therange of 1 to 14, or 0, or less than, equal to, or greater than about 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or about 14. These effectsdistinguish the current invention from prior art devices and methods.

To obtain the desired increase in Q_(max) or the decrease in IPSS, inone embodiment, a balloon coated with a therapeutic agent such as anantiproliferative or anti-inflammatory drug and one or morewater-soluble additives, as described herein, is positioned within thearea of a urethral stricture or within the prostate. For strictures, theballoon is then inflated to a diameter that is 1.0 to 20 times largerthan the native urethra (e.g., of a normative diameter of the treatedurethra), such as about 1.2 to 3 times larger. For BPH treatment, theballoon is inflated to a diameter that can be about 1.0 to 20 timeslarger than the native (undiseased) prostatic urethra, or about 1.2 to10 times larger. That is, the ratio of the inflated balloon diameter tothe normative diameter of the body lumen at the location of treatmentfor a urethral stricture can be from 1.2 to 3 and for BPH treatment canbe 1.2 to 10; the stretch ratio can be the same or different. Theballoon can be left inflated for 0.1 to 10 minutes to allow the drug tobe delivered to the urethra. In some embodiments, a scope such as acystoscope can be used to aid in the placement of the balloon. In someembodiments, the balloon catheter shaft can be within the lumen of thescope and in other embodiments it can be placed side by side with thescope. In some embodiments, the stricture or prostate can be predilatedwith a non-drug coated balloon prior to treatment by the drug coatedballoon. In some embodiments, the predilation balloon will be slightlyshorter than the treatment balloon, such as to ensure that the entirearea of the urethra or prostate that is predilated is later treated withthe drug coated balloon. In some embodiments, the lumen and/or the drugcoated balloon is flushed or soaked in water, saline, urine, or a watersolution including at least one water soluble additive prior to drugcoated balloon insertion. The drug coated balloon may be covered with asheath to provide protection to the coating during delivery to thetreatment site. The sheath can be removed from the balloon prior toinflating the balloon.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Other than the operating examples, or where otherwise indicated, allnumbers expressing quantities of components in a layer, reactionconditions, and so forth used in the specification and claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless otherwise indicated to the contrary, the numericalparameters set forth in this specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present disclosure.

EXAMPLES

Various embodiments of the present invention can be better understood byreference to the following Examples which are offered by way ofillustration. The present invention is not limited to the Examples givenherein.

Throughout the Examples, unless otherwise indicated, the stretch ratiowas calculated as the ratio of the diameter of the nominal balloon tothe normative diameter of the body lumen at the location of treatment.The normative diameter of the body lumen at the location of treatment isthe normal diameter for the body lumen at the location of treatment andcan be calculated as the average of the diameters of healthy tissueadjacent to the stricture, stenosis, or lesion, that is proximal anddistal of the stricture or stenosis or lesion of the lumen. The inflatedballoon diameter was about equal to the nominal balloon diameter for thepressure used during the inflation period, and was within 10% of thenominal balloon diameter.

Part I.

Example I-1. Preparation of Coating Solutions

Formulation 1: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, and 2-6 ml ethanol were mixed.

Formulation 2: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg uracil and 2-6 ml ethanol weremixed.

Formulation 3: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg uridine and 2-6 ml ethanol weremixed.

Formulation 4: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed.

Formulation 4a: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed, with a mass ratio of paclitaxel:PEG8 caprylic/capricglycerides:sucralose of 1:1:1.

Formulation 4b: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg sucralose and 2-6 ml ethanol weremixed, with a mass ratio of paclitaxel:PEG8 caprylic/capricglycerides:sucralose of 1:1:2.

Formulation 5: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8caprylic/capric glycerides, 25-300 mg creatinine and 2-6 ml ethanol weremixed.

Formulation 6: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG6caprylic/capric glycerides, 25-300 mg uracil and 2-6 ml ethanol weremixed.

Formulation 7: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgC6-ceramide and 2-6 ml ethanol were mixed.

Formulation 8: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgmonolaurin, 25-300 mg sucralose and 2-6 ml ethanol were mixed.

Formulation 9: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgsucralose and 2-6 ml ethanol were mixed.

Formulation 10: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8mono caprylate/caprate and 1-6 ml ethanol were mixed.

Formulation 11: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg PEG8mono caprylate/caprate, 25-300 mg sucralose and 1-6 ml ethanol weremixed.

Formulation 12: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgthymidine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 13: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mguridine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 14: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgcaffeine, and 1-6 ml (96/4 v/v) THF/water were mixed.

Formulation 15: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg18Crown6, and 1-6 ml ethanol were mixed.

Formulation 16: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg18Crown6, and 1-6 ml ethanol were mixed.

Formulation 17: 50-150 mg (0.06-0.18 mmole) paclitaxel, 10-100 mg18Crown6, 10-100 mg pentaerythritol ethoxylate (15/4) and 1-6 ml ethanolwere mixed.

Formulation 18: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgpentaerythritol ethoxylate (15/4), and 1-6 ml ethanol were mixed.

Formulation 19: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgtrimethylpropane ethoxylate (Mw˜1014)), and 1-6 ml ethanol were mixed.

Formulation 20: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgpentaerythritol ethoxylate (3/4), and 1-6 ml ethanol were mixed.

Formulation 21: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mg15Crown5, and 1-6 ml ethanol were mixed.

Formulation 22: 25-100 mg (0.03-0.12 mmole) paclitaxel, 25-300 mgthymidine, and 1-6 ml (90/10 v/v) THF/water were mixed.

Formulation 23: 50-150 mg (0.06-0.18 mmole) paclitaxel, 5-75 mgpentaerythritol ethoxylate (15/4), 10-200 mg pentaerythritol ethoxylate(3/4), and 1-6 ml ethanol were mixed.

Formulation 24: 50-150 mg (0.06-0.18 mmole) paclitaxel, 25-300 mgtrimethylpropane ethoxylate (Mw˜170)), and 1-6 ml ethanol were mixed.

Example I-2. Preclinical Study 1 & 2 Sample Preparation

Twenty-one balloon catheters (twelve 4 mm in diameter and 40 mm inlength, six 8 mm in diameter and 40 mm in length, three 20 mm indiameter and 50 mm in length) were inflated to 1 to 2 atmospherespressure and wiped with an ethanol wipe to clean the balloon surface.Next the balloons were coated using various formulations (1-6) fromExample I-1 with sufficient coating solution to achieve 2-4 microgrampaclitaxel per square mm of balloon surface. The balloons were thendried, folded, sheathed, packaged in a Tyvek pouch and ethylene oxidesterilized in preparation for animal testing.

Example I-3. Preclinical Study 1 & 2 Treatments

For this study male dogs were used. Baseline urethrograms were taken tomeasure the inner diameter of the urethra treatment sites before drugcoated balloon treatment. Drug coated balloon catheters prepared inExample I-2 were used with nonoverlapping treatments in the pelvic,bulbar, and distal urethra just proximal of the os penis. The os penisurethra was not treated. The treatment site diameters were approximately3.5-4.5 mm. The balloon catheters were chosen such that the stretchratio for the prostatic urethra balloons was approximately 4-10. For theanterior urethra, balloon catheters were chosen such that the stretchratio was approximately 1.8-2.3. Prior to inserting the catheterapproximately 5 mL of saline was used to flush the urethra. The 18-20 mmnominal diameter balloons were inflated in the prostatic urethra and the8 mm nominal diameter balloons were inflated in the anterior urethra.The 18 to 20 mm nominal diameter balloons were inflated to 4 atmospheresat the treatment sites for 10 min to release drug and additive, thendeflated and withdrawn from the dogs. The 8 mm nominal diameter balloonswere inflated to 12 atmospheres at the treatment sites for 10 min torelease drug and additive, then deflated and withdrawn from the dogs.The stretch ratio for the inflated 20 mm nominal diameter balloons was4.4 to 6.3. The stretch ratio for the inflated 8 mm nominal diameterballoons was 2.0 to 2.5. The amount of drug in the treated urethratissues of the sacrificed animal was measured after 4 hrs and 1 day andthe residual drug remaining on the balloon after use was analyzed.

Drug coated balloon catheters prepared in Example I-2 were inserted intothe left ureter and urethra of a female pig. The 4 mm nominal diameterballoons were inflated to 14 atmospheres in the ureters and the 8 mmballoons were inflated to 12 atmospheres in the urethra. The balloonswere inflated at the treatment sites for 10 min to release drug andadditive, then deflated and withdrawn from the pigs. The stretch ratiofor the 4 mm nominal diameter balloons was 2 to 2.5. The stretch ratiofor the 8 mm nominal diameter balloons was 2.0 to 2.5. The drugconcentration in the urethra and prostate tissues of the sacrificedanimal was measured after 4 hrs. The residual drug remaining on theballoon after use was analyzed.

Example I-4. Preclinical Study 1 & 2 Tissue and Balloon Residual DrugContent

The dog tissue drug concentration from the prostatic urethra sample inExample I-3, using Formulation 4a, was 0.4 μg/g at 4 hours. The dogtissue drug concentration from the prostate sample in Example I-3, usingFormulation 4a, was 0.367 μg/g at 4 hours. The dog tissue drugconcentration from the pelvic urethra samples in Example I-3, usingFormulation 4b, was 11.7 μg/g at 4 hours. The dog tissue drugconcentration from the bulbar urethra samples in Example I-3, usingFormulation 4a, was 25.2 μg/g at 4 hours. The dog tissue drugconcentration from the prostatic urethra sample in Example I-3, usingFormulation 4a, was 0.586 μg/g at 1 day. The dog tissue drugconcentration from the prostate sample in Example I-3, using Formulation4a, was 0.429 μg/g at 1 day. The dog tissue drug concentration from thepelvic urethra samples in Example I-3, using Formulation 4b, was 26.6μg/g at day 1. The dog tissue drug concentration from the distal urethrasamples in Example I-3, using Formulation 4a, was 2.04 μg/g at day 1.The residual balloon content as a percent of the original drug loadingfrom the samples in Example I-3, using Formulation 4a, ranged from45-87%.

The residual balloon content as a percent of the original drug loadingfrom the samples in Example I-3, using formulation 4b, ranged from83-85%.

At 4 hours the proximal (Formulation 4b) right ureter pig tissue drugconcentration from the samples in Example I-3 was 17.3 μg/g. At 4 hoursthe female pig urethra (Formulation 4a) drug concentration was 66.9μg/g. The residual balloon content as a percent of the original drugloading from the samples in Example I-3 ranged from 6-58%. The averageresidual balloon content for Formulation 4a was 52.8%. The averageresidual balloon content for Formulation 4b was 64.7%.

Example I-5. Preclinical Study 3 Sample Preparation

Twenty-three balloon catheters (twelve 8 mm in diameter and 40 mm inlength, six 10 mm in diameter and 40 mm in length, four 12 mm indiameter and 30 mm in length, and three 10 mm in diameter and 30 mm inlength) were inflated to 50% of their nominal inflation pressure andwiped with an ethanol wipe to clean the balloon surface. Next theballoons were coated using various formulations (1-6) in Example I-1with sufficient coating solution to achieve 2 microgram paclitaxel persquare mm of balloon surface. The balloons were then dried, folded,sheathed, packaged in a Tyvek pouch and ethylene oxide sterilized inpreparation for animal testing.

Example I-6. Preclinical Study 3 Treatments

For this study male dogs were used. Baseline retrograde urethrogramswere taken to measure the inner diameter of the urethra treatment sitesbefore drug coated balloon treatment. Drug coated balloon cathetersprepared in Example I-5 were used with nonoverlapping treatments in theprostatic, pelvic, bulbar, and distal urethra just proximal of the ospenis. The os penis urethra was not treated. The treatment sitediameters were approximately 2.1-8.5 mm. The balloon catheters werechosen such that the stretch ratio for the prostatic urethra balloons(the ratio of the nominal diameter of the balloon to the normativediameter of the target site) was planned to be approximately 1.7-3.4.For the anterior urethra, balloon catheters were chosen such that thestretch ratio was approximately 1.8-2.3. Prior to inserting the catheterapproximately 5 mL of saline was used to flush the urethra. The 12 mmnominal diameter balloons were inflated in the prostatic urethra and the8 and 10 mm nominal diameter balloons were inflated in the anteriorurethra. The 12 mm nominal diameter balloons were inflated to 9atmospheres at the treatment sites for 10 min to release drug andadditive, then deflated and withdrawn from the dogs. The 8 mm nominaldiameter balloons were inflated to 10 atmospheres at the treatment sitesfor 10 min to release drug and additive, then deflated and withdrawnfrom the dogs. The stretch ratio for the 12 mm nominal diameter balloonswas 2.0 to 3.0. The stretch ratio for the 8 and 10 mm nominal diameterballoons was 1.3 to 3.0. The amount of drug in the treated urethratissues of the sacrificed animal was measured after 1 and 7 days and theresidual drug remaining on the balloon after use was analyzed.

Example I-7. Preclinical Study 3 Tissue and Balloon Residual DrugContent

The dog tissue drug concentration from the samples in Example I-6 rangedfrom 4-176 μg/g at 1 day and 0.003-23 μg/g at 7 days. The residualballoon content as a percent of the original drug loading from thesamples in Example I-6 ranged from 5-98%.

Example I-8. Preclinical Study 4 Sample Preparation

One hundred eight balloon catheters (forty-two 8 mm in diameter and 20mm in length, twenty-seven 10 mm in diameter and 40 mm in length,twenty-five 12 mm in diameter and 40 mm in length, five 8 mm in diameterand 55 mm in length, nine 12 mm in diameter and 55 mm in length) wereinflated to 50% of their nominal inflation pressure and wiped with anethanol wipe to clean the balloon surface. Next the balloons were splitinto two groups; one group was coated using Formulation 1 andFormulation 4 from Example I-1 with sufficient coating solution toachieve 2 microgram paclitaxel per square mm of balloon surface, and theother group was coated using the same formulations from Example I-1 withsufficient coating solution to achieve 4 microgram paclitaxel per squaremm of balloon surface. The balloons were then dried, folded, sheathed,packaged in a Tyvek pouch and ethylene oxide sterilized in preparationfor animal testing.

Example I-9. Preclinical Study 4 Treatments

For this study male dogs were used. Baseline retrograde urethrogramswere taken to measure the inner diameter of the urethra treatment sitesbefore drug coated balloon treatment. Drug coated balloon cathetersprepared in Example I-8 were used with nonoverlapping treatments in theprostatic, pelvic, bulbar, and distal urethra just proximal of the ospenis. The os penis urethra was not treated. The treatment sitediameters were approximately 2.6-7.7 mm. The balloon catheters werechosen such that the stretch ratio for the prostatic urethra balloonswas planned to be approximately 2-4. For the anterior urethra, ballooncatheters were chosen such that the stretch ratio was approximately1.8-2.3. Prior to inserting the catheter approximately 5 mL of salinewas used to flush the urethra. 8 and 12 mm nominal diameter balloonswere inflated in the prostatic urethra and 8 mm nominal diameterballoons were inflated in the anterior urethra. The prostatic urethraballoons were inflated to 6-9 atmospheres at the treatment sites for 10min to release drug and additive, then deflated and withdrawn from thedogs. The 8 mm nominal diameter balloons were inflated to 10 atmospheresat the treatment sites for 10 min to release drug and additive, thendeflated and withdrawn from the dogs. The stretch ratio for theprostatic urethra balloons was 2.0 to 5, 10, 15, or 20. The stretchratio for the anterior urethra balloons was 1.1, 1.2, 1.3, 1.4, or 1.5to 1.75, 2.0, 2.25, 2.50, 2.75, 3.0. The urethra diameter and the amountof drug in the treated urethra tissues of the sacrificed animal wasmeasured after 1, 7 and 28 days and the residual drug remaining on theballoon after use was analyzed. At 28 days samples were taken forhistological evaluation to compare drug coated balloon tissue to plainold balloon and untreated tissue.

Example I-10. Preclinical Study 4 Pharmacokinetics, Balloon ResidualDrug Content, and Urethra Lumen Gain

The dog tissue average drug concentration from the samples in ExampleI-9 was 582 μg/g at 1 day, 0.347 μg/g at day 7, and 4 μg/g at day 28.The dog tissue average drug concentration from the 2 μg/g and 4 μg/gdose density Formulation 1 samples in Example I-9 was 20.34 μg/g and0.73 μg/g, respectively, at day 28. The dog tissue average drugconcentration from the 2 μg/g and 4 μg/g dose density Formulation 4samples in Example I-9 was 0.01 μg/g and 1.20 μg/g, respectively, at day28. The residual balloon content as a percent of the original drugloading from the samples in Example I-9 ranged from 0-60%. The averageresidual balloon content as a percent of the original drug loading fromthe 2 μg/g and 4 μg/g dose density Formulation 1 samples was 11.5% and2.4%, respectively. The average residual balloon content as a percent ofthe original drug loading from the 2 μg/g and 4 μg/g dose densityFormulation 4 samples was 12.2% and 19.9%, respectively. The meanurethral gain at 28 days, treatment site urethra diameter at 28 daysminus the urethral diameter at time of treatment, ranged from 1.6 mm toa lumen loss of 4.4 mm. Examination of the histology samples showed nodiscernable difference between the drug coated balloon treatments, plainballoon treatments, and untreated tissue.

Example I-11. Preclinical Study 5 Sample Preparation

Forty balloon catheters (twenty 6 mm in diameter and 20 mm in length,twenty 8 mm in diameter and 20 mm in length) were inflated to 50% oftheir nominal inflation pressure and wiped with an ethanol wipe to cleanthe balloon surface. Next the balloons were split into two groups; onegroup was coated using various formulations (1-6) in Example I-1 withsufficient coating solution to achieve 3.5 microgram paclitaxel persquare mm of balloon surface the other group was coated using variousformulations (1-6) in Example I-1 with sufficient coating solution toachieve 10 microgram paclitaxel per square mm of balloon surface. Theballoons were then dried, folded, sheathed, packaged in a Tyvek pouchand ethylene oxide sterilized in preparation for animal testing.

Example I-12. Preclinical Study 5 Treatments

For this study female pigs were used to allow for easier access to theureters. Before drug coated balloon treatments baseline uretergrams andurethrograms were taken to measure the inner diameters of the ureter andurethra treatment sites before treatment. The treatment site diameterswere approximately 4.0-6.0 mm. For the urethra, balloon catheters werechosen such that the stretch ratio was approximately 1.8-2.3. Drugcoated balloon catheters prepared in Example I-11 were used fornonoverlapping treatments. A controlled experiment was conducted toinvestigate two procedure parameters; balloon to urethra stretch,inflation time, and one product design feature; the drug dose density.The amount of drug in the treated urethra tissues of the sacrificedanimal was measured after 1 day and the residual drug remaining on theballoon after use was analyzed.

Example I-13. Preclinical Study 5 Balloon Residual Drug Content andTissue Drug Content

The pig tissue average drug concentration from the samples in ExampleI-12 was 12.5 μg/g at 1 day. The residual balloon content as a percentof the original drug loading from the samples in Example I-12 rangedfrom 1-52%.

Example I-14. Preclinical Study 6 Sample Preparation

Eighty-seven balloon catheters (thirty-seven 12 mm in diameter and 20 mmin length, fifty 8 mm in diameter and 20 mm in length) were inflated to50% of their nominal inflation pressure and wiped with an ethanol wipeto clean the balloon surface. Next the balloons were split into twogroups; one group was coated using various formulations (1-6) in ExampleI-1 with sufficient coating solution to achieve 3.5 microgram paclitaxelper square mm of balloon surface the other group was coated usingvarious formulations (1-6) in Example I-1 with sufficient coatingsolution to achieve 10 microgram paclitaxel per square mm of balloonsurface. The balloons were then dried, folded, sheathed, packaged in aTyvek pouch and ethylene oxide sterilized in preparation for animaltesting.

Example I-15. Preclinical Study 6 Treatments

For this study casted male pigs were used. Before drug coated balloontreatments baseline urethrograms were taken to measure the innerdiameter of the urethra treatment sites before treatment. Drug coatedballoon catheters prepared in Example I-14 were used with nonoverlappingtreatments. Prior to inflation 5-10 mL of saline was used to flush theurethra. A controlled experiment was conducted to investigate the effectof double inflation and drug dose density on the amount of drug in thetreated urethra tissues. The tissue drug content was measured after 1day and 28 days and the residual drug remaining on the balloon after usewas analyzed. Histology samples were taken at 28 days to compare the twodifferent drug dose density catheter groups

Example I-16. Preclinical Study 5 Balloon Residual Drug Content andTissue Drug Content

The pig tissue average drug concentration from the samples in ExampleI-14 was 83 ng/g at 1 day and 2.5 ng/g at 28 days. The residual ballooncontent as a percent of the original drug loading from the samples inExample I-14 ranged from 19-73%.

Example I-17. Preclinical Study 7 Sample Preparation

Fifty-seven balloon catheters (forty-three 8 mm in diameter and 20 mm inlength, fourteen 20 mm in diameter and 60 mm in length) were inflated to50% of their nominal inflation pressure and wiped with an ethanol wipeto clean the balloon surface. The balloons were coated using variousformulations (1-6) in Example I-1 with sufficient coating solution toachieve 3.5 microgram paclitaxel per square mm of balloon surface. Theballoons were then dried, folded, sheathed, packaged in a Tyvek pouchand ethylene oxide sterilized in preparation for animal testing.

Example I-18. Preclinical Study 7 Treatments

For this study male dogs were used. These treatments were conductedunder direct visualization using a 2.4 mm outer diameter endoscope. Theendoscope utilized constant saline irrigation to flush visualobstructions away from the field of view, thus the treatment zones wereconstantly being flushed at all times. The first step in the treatmentwas to use cutting balloons (balloon catheters that have blades runninglongitudinally along the length of the balloon) in the prostaticurethra, middle urethra, and distal urethra. Next, uncoated balloonswere used to dilate the treatment locations where the cutting balloonswere used. Then baseline urethrograms were taken to measure the innerdiameter of the urethra treatment sites before drug coated balloontreatment. Finally, drug coated balloon catheters prepared in ExampleI-17 and uncoated balloon catheters (as controls) were used. The 20 mmnominal diameter balloons were used in the prostatic urethra and the 8mm nominal diameter balloons were used in the anterior urethra. Theprostatic urethra balloons were inflated to 4-5 atmospheres at thetreatment sites for 2 min to release drug and additive, then deflatedand withdrawn from the dogs. The 8 mm nominal diameter balloons wereinflated to 10 atmospheres at the treatment sites for 2 min to releasedrug and additive, then deflated and withdrawn from the dogs. Thestretch ratio for the prostatic urethra balloons was 2.9 to 9.7. Thestretch ratio for the anterior urethra balloons was 1.5 to 2.8. Thetissue drug content was measured after 3 day, 7 days, and 28 days andthe residual drug remaining on the balloon after use was analyzed.Histology samples were taken at 3 and 28 days to compare direct drugcoated balloon treatment to cutting balloon pretreatment followed bydrug coated balloon treatment.

Example I-19. Preclinical Study 7 Pharmacokinetics, Balloon ResidualDrug Content, Lumen Gain, and Histology

The dog tissue average drug concentration from the samples in ExampleI-18 was 100 μg/g at day 3 and 62 μg/g at day 7 and 33 μg/g at day 28.The residual balloon content as a percent of the original drug loadingfrom the samples in Example I-18 ranged from 2-50%.

Example I-20. Preclinical Study 8 Sample Preparation

Thirty-nine balloon catheters (8 mm in diameter and 30 mm in length)were inflated to 3 atmospheres and wiped with an ethanol wipe to cleanthe balloon surface. The balloons were coated using Formulations 18, 19,and 23 from Example I-1 with sufficient coating solution to achieve 2.5microgram paclitaxel per square mm of balloon surface. The balloons werethen dried, folded, sheathed, packaged in a Tyvek pouch and ethyleneoxide sterilized in preparation for animal testing.

Example I-21. Preclinical Study 8 Treatments

For this study male dogs were used. Baseline urethrograms were taken tomeasure the inner diameter of the urethra treatment sites before drugcoated balloon treatment. The treatment site diameters wereapproximately 3.5-4.5 mm. The balloon catheters were chosen such thatthe stretch ratio for the anterior urethra balloons was approximately1.8-2.3. Drug coated balloon catheters prepared in Example I-20 wereused with nonoverlapping treatments in the pelvic, bulbar, and distalurethra just proximal of the os penis. The os penis urethra was nottreated. Prior to inserting the catheter approximately 5 mL of salinewas used to flush the urethra. The 8 mm nominal diameter balloons wereinflated to 12 atmospheres at the treatment sites for 2 min to releasedrug and additive, then deflated and withdrawn from the dogs. Thestretch ratio for the anterior urethra balloons was approximately2.0-2.5. The tissue drug content was measured after 1 day and theresidual drug remaining on the balloon after use was analyzed.

Example I-22. Preclinical Study 8 Tissue Drug Content and BalloonResidual Drug Content

The dog tissue drug concentration from the pelvic urethra samples inExample I-21 was 0.305, 1.17, 17.3, 33.4 μg/g at day 1. The dog tissuedrug concentration from the bulbar urethra samples in Example I-21 was0.28, 4.31, 44.5, 57.8 μg/g at day 1. The dog tissue drug concentrationfrom the distal urethra samples in Example I-21 was 7.37, 38.9, 238, 268μg/g at day 1. The average drug concentration from Formulations 18, 19,and 23 was 6.5, 33.6, and 137.7 μg/g, respectively, at day 1. Theresidual balloon content as a percent of the original drug loading fromthe samples in Example I-21 ranged from 20.4-81.7%. The average residualballoon content as a percentage of the original drug loading fromFormulations 18, 19, and 23 was 57.7%, 68.7%, and 51.9%, respectively.

Example I-23. Bench-Top Drug Release Testing Sample Preparation

Forty-nine balloon catheters (thirty-one 8 mm in diameter and 30 mm inlength, six 10 mm in diameter and 20 mm in length, thirteen 12 mm indiameter and 20 mm in length) were inflated to 3 atmospheres and wipedwith an ethanol wipe to clean the balloon surface. The balloons werecoated using various formulations (1-34) in Example I-1 with sufficientcoating solution to achieve either 2.5 or 3.5 microgram paclitaxel persquare mm of balloon surface. The balloons were then dried, folded,sheathed, packaged in a Tyvek pouch and ethylene oxide sterilized inpreparation for bench testing.

Example I-24. Bench-Top Drug Release Testing

A bench top drug release apparatus was developed that consisted of a 10inch long by 2 inch diameter cylindrical vessel placed inside atemperature controlled water bath. The cylindrical vessel was filledwith 0.9% saline and maintained at 37° C. for the testing. An 8 French(i.e., wherein 3 French is 1 mm) by 13 cm long introducer sheathpenetrated the top of the cylindrical vessel and was used as a conduitto pass balloon catheter samples into the cylindrical vessel. Thesamples developed in Example I-22 were individually passed into thecylindrical vessel where they soaked for 1 minute prior to beinginflated to 10 atmospheres for 1 minute and then withdrawn. Theremaining drug on the balloon was analyzed to determine how much drugwas released. The amount of drug released during this testing rangedfrom 37% to 97%.

Part II.

Example II-1. Bench Testing with Pig Urethras

The purpose of this study was to evaluate if a necked balloon designcould prevent movement during inflation in an anatomical model.

Intact male porcine bladders and urethras were obtained from a localresearch facility. Balloon catheters were constructed with 20 mmdiameter×80 mm length 7233 PEBAX® balloons. Two balloon neck sectionswere created in the balloon using an UHMWPE suture. The suture was tiedto the balloon at the desired location to prevent balloon expansion,thereby creating necks. Necks were positioned symmetrically along thelength of the balloon splitting the 80 mm length into three about 20 mmbody sections. Neck sections were sized to 10 mm lengths and were about8 mm in diameter. Neck section lengths are measured from one larger bodysection to the adjacent larger body section. Balloons were attached to10 Fr catheter shafts and were pleated/folded and placed in a sheath tofacilitate insertion.

Intact pig urethra and bladders were placed in a 37° C. water bath tosimulate body temperature. Balloon catheters were inserted through theurethra and positioned with the distal edge of the balloon located atthe bladder neck. Balloons were inflated until visual evidence of aurethral split or to the maximum rated burst pressure (RBP) of 6 atm.Balloons were deflated immediately after the urethral split wasconfirmed. Inflation speed was varied across samples using 0.5 atm/min,1.0 atm/min, and 2.0 atm/min. Total inflation time was between 3 and 10minutes depending on the inflation speed.

Necked balloons for this study were able to prevent balloon movementduring inflation. The stretch ratio of the inflated balloon diameter tothe normative prostatic urethral diameter was between about 3.0-3.5.Additionally, this study indicated that inflation rate played a role inballoon movement. By inflating the balloon slower, and allowing thetissue to stress relax and yield, migration of the balloon into thebladder was further minimized. Rates of 0.5 atm/min and 1.0 atm/min hadless balloon movement during inflation.

Part III. Testing of Drug Coated Balloons in Urethral Strictures ofHuman Subjects.

The following Examples include embodiments of the use of medical deviceswith drug coating within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Materials. Drug coated balloon catheters with a dose density of 3.5 μgof paclitaxel per millimeter squared were used to treat human subjectsthat had stricture disease in a clinical study. The drug coated ballooncatheters had nominal diameters of 6, 8, 10, 12, and 14 mm and lengthsof 30 and 50 mm at nominal pressure of 6 atm. The paclitaxel (PTX)dosing per balloon size can be seen in Table 6.

TABLE 6 Diameter Paclitaxel (PTX) dosing per balloon size. (mm) 30 mmLength 50 mm Length 6 1979 μg PTX 3299 μg PTX 8 2639 μg PTX 4398 μg PTX10 3299 μg PTX 5498 μg PTX 12 3958 μg PTX 6597 μg PTX 14 4618 μg PTX7697 μg PTX

The drug coated balloon catheters had a dual lumen shaft design with asingle inflatable balloon. One lumen was sized to accommodate a 0.038″guide wire lumen. The other lumen was the inflation port lumen andallows the balloon to be inflated with mixture of saline and contrastfluid. The drug coated balloon catheter had a manifold with two Luerstyle connections, one connection was compatible with an inflationsyringe, the other allowed the guidewire to protrude out of the manifoldso the balloon catheter could freely slide onto the guidewire. The 6 and8 mm drug coated balloon catheters had a rated burst pressure of 12atmospheres. The 10, 12, and 14 mm drug coated balloon catheters had arated burst pressure of 10 atmospheres. The balloon was made ofpolyamide.

Uroflowemetry (Q_(max) measurement). Uroflowmetry is performed byurinating into a special urinal, toilet, or disposable device that has ameasuring device built into it. The parameter, Q_(max), is the maximumflow rate measured during a Uroflowmetery test. This method was usedprior to treatment (baseline) and at follow-up visits of 1, 3, 6, and 12months to demonstrate the longevity of the treatment.

International Prostate Symptom Score (IPSS). The IPSS is based on theanswers to eight questions—seven regarding disease symptoms and onequestion related to the patient's quality of life: 1) IncompleteEmptying; How often have you had the sensation of not emptying yourbladder? 2) Frequency; How often have you had to urinate less than everytwo hours? 3) Intermittency; How often have you found you stopped andstarted again several times when you urinated? 4) Urgency; How oftenhave you found it difficult to postpone urination? 5) Weak Stream; Howoften have you had a weak urinary stream? 6) Straining; How often haveyou had to strain to start urination? 7) Nocturia; How many times didyou typically get up at night to urinate? 8) Quality of Life Due toUrinary Symptoms; If you were to spend the rest of your life with yoururinary condition just the way it is now, how would you feel about that?Although the IPSS was developed for BPH it can be applied to otherbladder outlet obstructive diseases such as stricture to determine ifobstructive symptoms are improved after a medical treatment. For thesymptom questions, the patient is asked to choose the rating that bestrepresents their condition. The scale ranges from 0 to 5, with 5representing the most symptomatic disease. The seven symptom scores aresummed to give an overall maximum possible score of 35. The answer tothe quality of life question is scored on a scale of 0 to 6. Accordingto these scoring systems, the scores can be categorized as follows:symptoms are mild if the score is 7 or less; symptoms are moderate ifthe score is 8 to 19; and symptoms are severe if the score is 20 to 35.This questionnaire was given prior to treatment (baseline) and atfollow-up visits of 1, 3, 6, and 12 months to demonstrate the longevityof the treatment.

Example III-1. Human Clinical Subject A Treated with an UncoatedPredilation Balloon Followed by an 8 mm Nominal Diameter Drug CoatedBalloon Catheter

Subject A had a 1.5 cm length by 2.5 mm diameter stricture in hisanterior urethra. Specifically, the bulbar portion of the anteriorurethra. This was determined by conducting a retrograde urethragram. Thehuman clinical subject had a baseline Q_(max) (maximum urine flow rate)of 4.0 mL/second and a baseline IPSS score of 25. First a cystoscope wasinserted into the urethra. Then a guidewire was inserted into theworking channel of the cystoscope. Next a predilation balloon that had anominal diameter of 7 mm and a length of 20 mm was inserted into theurethra over the guidewire and positioned so the balloon crossed thestricture. The predilation balloon was inflated to 14 atmospheres with asyringe that had a pressure gage on it. The syringe contained a mixtureof saline and contrast media. A fluoroscopic image was acquired toensure the balloon had a uniform expansion. Once this was confirmed theballoon was deflated and withdrawn from the urethra. Next a drug coatedballoon that had a nominal diameter of 8 mm and a length of 30 mm wasinserted into the urethra over the guidewire. The drug coated balloonwas positioned such that the balloon body completely covered thepredilated stricture area. The drug coated balloon was held in positionfor at least 1 minute prior to inflating to hydrate the coating. Thenthe drug coated balloon was inflated with a mixture of saline andcontrast media using the syringe that had a pressure gage on it. Theballoon was inflated to 11 atmospheres, achieved an inflated diameter of8.5 mm, and was held at the inflation pressure for 5 minutes. Then theballoon was deflated and withdrawn from the human subject. The stretchratio for the 8 mm nominal diameter drug coated balloon was 1.1 to 1.4.The diameter of the dilated stricture was 7 mm after dilation. Theresidual drug remaining on the balloon after use was analyzed. Theresidual amount of paclitaxel left on the balloon was 158 μg (6 percentof the initial drug load). The human clinical subject had follow-upvisits at 14, 30, 90, 180, and 365 days to measure maximum urine flowrate and IPSS score. Additionally, the urethral caliber of the humanclinical subject was assessed at 6 months to determine if the urethrawas greater than 16 French (5.3 mm) by visualizing and passing aflexible cystoscope past the previously treated area. The human clinicalsubject had a maximum urine flow rate of 50.0, 44.0, 35.0, and 32.0mL/second at follow-up visits of 14, 90, 180, and 365 days respectively.The human clinical subject had an IPSS of 6, 4, and 2 at follow-upvisits of 30, 90, and 180 days respectively. The human clinical subjecthad a urethra caliber greater than 16 French (5.3 mm) at 6 months.

Example III-2. Human Clinical Subject B Treated with an UncoatedPredilation Balloon Followed by a 10 mm Nominal Diameter Drug CoatedBalloon Catheter

Subject B had a 1.5 cm length by 2.0 mm diameter stricture in hisanterior urethra. Specifically, the bulbar portion of the anteriorurethra. This was determined by conducting a retrograde urethragram. Thehuman clinical subject had a baseline Qmax (maximum urine flow rate) of2.0 mL/second and a baseline IPSS score of 24. First a cystoscope wasinserted into the urethra. Then a guidewire was inserted into theworking channel of the cystoscope. Next a predilation balloon that had anominal diameter of 10 mm and a length of 20 mm was inserted into theurethra over the guidewire and positioned so the balloon crossed thestricture. The predilation balloon was inflated to 20 atmospheres with asyringe that had a pressure gage on it. The syringe contained a mixtureof saline and contrast media. A fluoroscopic image was acquired toensure the balloon had a uniform expansion. Once this was confirmed theballoon was deflated and withdrawn from the urethra. Next a drug coatedballoon that had a nominal diameter of 10 mm and a length of 30 mm wasinserted into the urethra over the guidewire. The drug coated balloonwas positioned such that the balloon body completely covered thepredilated stricture area. The drug coated balloon was held in positionfor at least 1 minute prior to inflating to hydrate the coating. Thenthe drug coated balloon was inflated with a mixture of saline andcontrast media using the syringe that had a pressure gage on it. Theballoon was inflated to 10 atmospheres for 5 minutes. Then the balloonwas deflated and withdrawn from the human subject. The stretch ratio forthe 10 mm nominal diameter drug coated balloon was 1.3 to 1.5. Thediameter of the dilated stricture was 10 mm after dilation. The residualdrug remaining on the balloon after use was analyzed. The residualamount of paclitaxel left on the balloon was 315 μg (9.5 percent of theinitial drug load). The human clinical subject had follow-up visits at14, 30, 90, and 180 days to measure maximum urine flow rate and IPSSscore. Additionally, the urethral caliber of the human clinical subjectwas assessed at 6 months to determine if the urethra was greater than 16French (5.3 mm) by visualizing and passing a flexible cystoscope pastthe previously treated area. The human clinical subject had a maximumurine flow rate of 19.0, 13.0, 18.0, and 16.0 mL/second at follow-upvisits of 14, 30, 90, and 180 days respectively. The human clinicalsubject had an IPSS of 2 at the 30 day follow-up visit. The humanclinical subject had a urethra caliber greater than 16 French (5.3 mm)at 6 months.

Example III-3. Human Clinical Subject C Treated with Direct VisualInternal Urethrotomy (DVIU) Followed by a 10 mm Nominal Diameter DrugCoated Balloon Catheter

Subject C had a 1.9 cm length by 2.0 mm diameter stricture in hisanterior urethra. Specifically, the bulbar portion of the anteriorurethra. This was determined by conducting a retrograde urethragram. Thehuman clinical subject had a baseline Q_(max) (maximum urine flow rate)of 1.0 mL/second and an IPSS score of 24. First a resectoscope wasinserted into the urethra. Then a guidewire was inserted into theworking channel of the resectoscope. Next the resectoscope was used tocut the urethra at the 12 o'clock position to open the stricturedurethra to greater than 20 French (6.7 mm). The length of the cut wasthe length of the stricture. Next a drug coated balloon that had anominal diameter of 10 mm and a length of 30 mm was inserted into theurethra over the guidewire. The drug coated balloon was positioned suchthat the balloon body completely covered the cut stricture area. Thedrug coated balloon was held in position for at least 1 minute prior toinflating to hydrate the coating. Then the drug coated balloon wasinflated with a mixture of saline and contrast media using the syringethat had a pressure gage on it. The balloon was inflated to 10atmospheres for 5 minutes. Then the balloon was deflated and withdrawnfrom the human subject. The stretch ratio for the 10 mm nominal diameterdrug coated balloon was 1.3 to 1.5. The diameter of the dilatedstricture was 9.5 mm after dilation. The residual drug remaining on theballoon after use was analyzed. The residual amount of paclitaxel lefton the balloon was 264 μg (8 percent of the initial drug load. The humanclinical subject had follow-up visits at 14, 30, 90, and 180 days tomeasure maximum urine flow rate and IPSS score. Additionally, theurethral caliber of the human clinical subject was assessed at 6 monthsto determine if the urethra was greater than 16 French (5.3 mm) byvisualizing and passing a flexible cystoscope past the previouslytreated area. The human clinical subject had a maximum urine flow rateof 52.0, 52.0, 47.0, and 22.0 mL/second at follow-up visits of 14, 30,90, and 180 days respectively. The human clinical subject had an IPSS of0 at the 30 day follow-up visit. The human clinical subject had aurethra caliber greater than 16 French (5.3 mm) at 6 months.

Example III-4. Human Clinical Subject D Treated Directly with a DrugCoated Balloon Catheter

Subject D had a 1.7 cm length by 2.5 mm diameter stricture in hisanterior urethra. Specifically, the bulbar portion of the anteriorurethra. This was determined by conducting a retrograde urethragram. Thehuman clinical subject had a baseline Q_(max) (maximum urine flow rate)of 3.0 mL/second and a baseline IPSS score of 27. First a cystoscope wasinserted into the urethra. Then a guidewire was inserted into theworking channel of the cystoscope. Next a drug coated balloon that had anominal diameter of 10 mm and a length of 30 mm was inserted into theurethra over the guidewire. The drug coated balloon was positioned suchthat the balloon body centered on the stricture. The drug coated balloonwas held in position for at least 1 minute prior to inflating to hydratethe coating. Then the drug coated balloon was inflated with a mixture ofsaline and contrast media using the syringe that had a pressure gage onit. The balloon was inflated to 10 atmospheres for 5 minutes. Then theballoon was deflated and withdrawn from the human subject. The stretchratio for the 10 mm nominal diameter drug coated balloon was 1.2 to 1.4.The diameter of the dilated stricture was 8 mm after dilation. Theresidual drug remaining on the balloon after use was analyzed. Theresidual amount of paclitaxel left on the balloon was 99 μg (3 percentof the initial drug load). The human clinical subject had follow-upvisits at 14, 30, 90, 180, and 365 days to measure maximum urine flowrate and IPSS score. Additionally, the urethral caliber of the humanclinical subject was assessed at 6 months to determine if the urethrawas greater than 16 French (5.3 mm) by visualizing and passing aflexible cystoscope past the previously treated area. The human clinicalsubject had a maximum urine flow rate of 40.0, 37.0, 36.0, and 31.0mL/second at follow-up visits of 14, 90, 180, and 365 days respectively.The human clinical subject had an IPSS of 4, 2, 3, and 2 at follow-upvisits of 30, 90, 180, and 365 days respectively. The human clinicalsubject had a urethra caliber greater than 16 French (5.3 mm) at 6months.

Part IV. Testing of Drug Coated Balloons to Treat Benign ProstaticHyperplasia in Human Subjects.

Materials. Drug coated balloon catheters with a dose density of 2.4 μgof paclitaxel per millimeter squared were used to treat human subjectsthat had stricture disease in a clinical study. The drug coated ballooncatheters had nominal diameters of 30, 35, 40, and 45 mm and dilationlengths of 30, 35, 40, 45, and 50 mm at a nominal inflation pressure of2 atm. The paclitaxel (PTX) dosing per balloon size can be seen in Table7.

TABLE 7 Paclitaxel (PTX) dosing per balloon size. Diameter 30 mm 35 mm40 mm 45 mm 50 mm (mm) Length Length Length Length Length 30 9586 μg11004 μg 12421 μg 13839 μg 15256 μg PTX PTX PTX PTX PTX 35 12403 μg13915 μg 15238 μg 16561 μg 18073 μg PTX PTX PTX PTX PTX 40 15220 μg16543 μg 18055 μg 19567 μg 20890 μg PTX PTX PTX PTX PTX 45 18037 μg19455 μg 20872 μg 22290 μg 23707 μg PTX PTX PTX PTX PTX

The drug coated balloon catheters had a single lumen shaft design with asingle inflatable balloon. The single lumen was the inflation port lumenthat allows the balloon to be inflated with a mixture of saline andcontrast fluid. The drug coated balloon catheter shaft had a manifoldwith a Luer-style connection that was compatible with an inflationsyringe. The matrix of drug coated balloon catheters had a rated burstpressure of 4 atmospheres. Each drug coated balloon catheter had fourdistinct balloon features that provided special functionality. The fourfeatures were the proximal balloon lobe, the balloon neck, distalballoon lobe and the Coude tip. The proximal balloon lobe dilates theprostatic urethra when the balloon is inflated. The balloon neck anchorsinto the bladder neck during balloon inflation and prevents migration ofthe proximal balloon lobe into the bladder. The balloon neck isreinforced with ultra high molecular weight high density polyethylene(UHMHDPE) fibers that wrap around the balloon neck and are fixed inplace. The balloon neck reinforcement ensures the balloon neck does notgrow in diameter as the balloon is inflated. The distal balloon lobe isused for positioning and also provides dilation of the bladder neck andany intra prostatic protrusion present during balloon inflation. Theballoon is made of a higher durometer polyethylene oxide polyamide blockcopolymer (74D PEBAX®). The Coude tip is a specially curved tip thatallows the catheter to be tracked in the prostatic urethra. The Coudetip was made of silicone rubber. The balloon portion of the catheter waspleat and folded down to a caliber of 19 French. Each catheter had adelivery sheath placed over the catheter. The delivery sheath had twofunctions. One was to cover and protect the balloon. The other is toform a smooth cylindrical catheter body that allows the balloon catheterto be tracked into the urethra and positioned into the prostaticurethra.

Uroflowemetry (Q_(max) measurement) and International Prostate SymptomScore (IPSS) were measured using the techniques described herein in PartIII.

Example IV-1. Treatment of Benign Prostate Hyperplasia with a 35 mm by35 mm Drug Coated Balloon Catheter

Human subject A had a 3.5 cm length prostatic urethra, 3.7 cm widthprostate and 4.0 cm height prostate. The subject's prostate size was 38grams. This was determined by conducting trans rectal ultrasound (TRUS).The human clinical subject had a baseline Q_(max) (maximum urine flowrate) of 5.0 mL/second and a baseline IPSS score of 27. First acystoscope was inserted into the urethra to survey for urethrastricture, view and assess prostatic obstruction due to BPH, and to alsogather fluoroscopy images of anatomical landmarks such as the bladderneck and the external sphincter. Then the cystoscope was removed, andthe drug coated balloon was inserted into the urethra and tracked so theCoude tip was in the bladder. Next the delivery sheath was removed toexpose the drug coated balloon and the cystoscope was inserted side byside with the catheter shaft. Next the position of the drug coatedballoon was slightly adjusted such that the proximal bond of the balloonwas adjacent to the external sphincter. The balloon was held uninflatedfor at least 1 minute prior to inflating to hydrate the drug coating.Then the drug coated balloon was inflated with a mixture of saline andcontrast media using the syringe with pressure gage. The balloon wasinflated till the anterior commissure of the prostate was separated.This occurred at a pressure of 2 atmospheres. When the anteriorcommissure was split the pressure dropped because the balloon expandedfurther. The balloon was inflated further to 4 atmospheres and held for10 minutes. Then the balloon was deflated, and the delivery sheath wasinserted into the urethra to recapture the balloon into it. The videoimage from the cystoscope showed the prostatic urethra was at least12-22 mm after dilation. Finally, the catheter was withdrawn from thehuman subject. The stretch ratio for the 35 mm nominal diameter drugcoated balloon was 4.4 to 4.8. The residual drug remaining on theballoon after use was analyzed. The residual amount of paclitaxel lefton the balloon was 214 μg (3 percent of the initial drug load). Thehuman clinical subject had follow-up visits at 14, 30, 90, 180, and 365days to measure maximum urine flow rate and IPSS score. The humanclinical subject had a maximum urine flow rate of 40.0, 37.0, 36.0, and31.0 mL/second at follow-up visits of 14, 90, 180, and 365 daysrespectively. The human clinical subject had an IPSS of 4, 2, 3, and 2at follow-up visits of 30, 90, 180, and 365 days respectively.

Example IV-2. Treatment of Benign Prostate Hyperplasia with a 35 mm by45 mm Drug Coated Balloon Catheter

Human subject B had a 4.6 cm length prostatic urethra, 3.9 cm widthprostate and 4.1 cm height prostate. The subject's prostate size was72.5 grams. This was determined by conducting trans rectal ultrasound(TRUS). The human clinical subject had a baseline Q_(max) (maximum urineflow rate) of 14.0 mL/second and a baseline IPSS score of 19. First acystoscope was inserted into the urethra to survey for urethrastricture, to view and assess prostatic obstruction due to BPH, and toalso gather fluoroscopy images of anatomical landmarks such as thebladder neck and the external sphincter. Then the cystoscope wasremoved, and the drug coated balloon was inserted into the urethra andtracked so the Coude tip was in the bladder. Next the delivery sheathwas removed to expose the drug coated balloon and the cystoscope wasinserted side by side with the catheter shaft. Next the position of thedrug coated balloon was slightly adjusted such that the proximal bond ofthe balloon was adjacent to the external sphincter. The balloon was helduninflated for at least 1 minute prior to inflating to hydrate the drugcoating. Then the drug coated balloon was inflated with a mixture ofsaline and contrast media using the syringe with pressure gage. Theballoon was inflated till the anterior commissure of the prostate wasseparated. This occurred at a pressure of 2 atmospheres. When theanterior commissure was split the pressure dropped because the balloonexpanded further. The balloon was inflated further to 4 atmospheres andheld for 10 minutes. Then the balloon was deflated, and the deliverysheath was inserted into the urethra to recapture the balloon into it.The video image from the cystoscope showed the prostatic urethra was atleast 20-30 mm after dilation. Finally, the catheter was withdrawn fromthe human subject. The stretch ratio for the 35 mm nominal diameter drugcoated balloon was 4.4 to 4.8. The residual drug remaining on theballoon after use was analyzed. The residual amount of paclitaxel lefton the balloon was 167 μg (3 percent of the initial drug load). Thehuman clinical subject had follow-up visits at 14, 30, 90, 180, and 365days to measure maximum urine flow rate and IPSS score. The humanclinical subject had a maximum urine flow rate of 23.0, 24.0, 25.0, 21.0mL/second at follow-up visits of 14, 90, 180, and 365 days respectively.The human clinical subject had an IPSS of 7, 7, 6, and 5 at follow-upvisits of 30, 90, 180, and 365 days respectively.

Example IV-3. Treatment of Benign Prostate Hyperplasia with a 40 mm by45 mm Drug Coated Balloon Catheter

Human subject C had a 4.8 cm length prostatic urethra, 5.0 cm widthprostate and 3.9 cm height prostate. The subject's prostate size was 50grams. This was determined by conducting trans rectal ultrasound (TRUS).The human clinical subject had a baseline Qmax (maximum urine flow rate)of 12.0 mL/second and a baseline IPSS score of 29. First a cystoscopewas inserted into the urethra to survey for urethra stricture, to viewand assess prostatic obstruction due to BPH, and to also gatherfluoroscopy images of anatomical landmarks such as the bladder neck andthe external sphincter. Then the cystoscope was removed, and the drugcoated balloon was inserted into the urethra and tracked so the Coudetip was in the bladder. Next the delivery sheath was removed to exposethe drug coated balloon and the cystoscope was inserted side by sidewith the catheter shaft. Next the position of the drug coated balloonwas slightly adjusted such that the proximal bond of the balloon wasadjacent to the external sphincter. The balloon was held uninflated forat least 1 minute prior to inflating to hydrate the drug coating. Thenthe drug coated balloon was inflated with a mixture of saline andcontrast media using the syringe with pressure gage. The balloon wasinflated till the anterior commissure of the prostate was separated.This occurred at a pressure of 2 atmospheres. When the anteriorcommissure was split the pressure dropped because the balloon expandedfurther. The balloon was inflated further to 4 atmospheres and held for10 minutes. Then the balloon was deflated, and the delivery sheath wasinserted into the urethra to recapture the balloon into it. The videoimage from the cystoscope showed the prostatic urethra was at least23-33 mm after dilation. Finally, the catheter was withdrawn from thehuman subject. The stretch ratio for the 40 mm nominal diameter drugcoated balloon was 4.0 to 5.0. The residual drug remaining on theballoon after use was analyzed. The residual amount of paclitaxel lefton the balloon was 312 μg (3 percent of the initial drug load). Thehuman clinical subject had follow-up visits at 14, 30, 90, 180, and 365days to measure maximum urine flow rate and IPSS score. The humanclinical subject had a maximum urine flow rate of 21.0, 25.0, 26.0, and23.0 mL/second at follow-up visits of 14, 90, 180, and 365 daysrespectively. The human clinical subject had an IPSS of 12, 8, 6, and 4at follow-up visits of 30, 90, 180, and 365 days respectively.

Example IV-4. Treatment of Benign Prostate Hyperplasia with a 35 mm by35 mm Uncoated Balloon Catheter Followed a 40 mm by 45 mm Drug CoatedBalloon Catheter

Human subject D had a 4.1 cm length prostatic urethra, 3.7 cm widthprostate and 2.6 cm height prostate. The subject's prostate size was 21grams. This was determined by conducting trans rectal ultrasound (TRUS).The human clinical subject had a baseline Q_(max) (maximum urine flowrate) of 14.0 mL/second and a baseline IPSS score of 33. First acystoscope was inserted into the urethra to survey for anterior urethrastricture and to also gather fluoroscopy images of anatomical landmarkssuch as the bladder neck and the external sphincter. Then the cystoscopewas removed, and the uncoated balloon catheter was inserted into theurethra and tracked so the Coude tip was in the bladder. Next thedelivery sheath was removed to expose the uncoated balloon and thecystoscope was inserted side by side with the catheter shaft. Next theposition of the uncoated balloon was slightly adjusted such that theproximal bond of the balloon was adjacent to the external sphincter.Then the uncoated balloon was inflated with a mixture of saline andcontrast media using the syringe with pressure gage. The balloon wasinflated till the anterior commissure of the prostate was separated.This occurred at a pressure of 2 atmospheres. When the anteriorcommissure was split the pressure dropped because the balloon expandedfurther. The balloon was inflated further to 3 atmospheres and held for2 minutes. Then the cystoscope was removed, and the uncoated balloon wasrecaptured using the delivery sheath and removed. Next the drug coatedballoon was inserted into the urethra and tracked so the Coude tip wasin the bladder. Then the delivery sheath was removed to expose the drugcoated balloon and the cystoscope was inserted side by side with thecatheter shaft. Next the position of the drug coated balloon wasslightly adjusted such that the proximal bond of the balloon wasadjacent to the external sphincter. The balloon was held uninflated forat least 1 minute prior to inflating to hydrate the drug coating. Thenthe drug coated balloon was inflated with a mixture of saline andcontrast media using the syringe with pressure gage. The balloon wasinflated to 4 atmospheres and held for 10 minutes. The video image fromthe cystoscope showed the prostatic urethra was at least 20-30 mm afterdilation. Then the balloon was deflated, and the delivery sheath wasinserted into the urethra to recapture the balloon into it. Finally, thecatheter was withdrawn from the human subject. The stretch ratio for the40 mm nominal diameter drug coated balloon was 4.0 to 5.0. The residualdrug remaining on the balloon after use was analyzed. The residualamount of paclitaxel left on the balloon was 247 μg (5 percent of theinitial drug load). The human clinical subject had follow-up visits at14, 30, 90, 180, and 365 days to measure maximum urine flow rate andIPSS score. The human clinical subject had a maximum urine flow rate of27.0, 32.0, 36.0, and 32.0 mL/second at follow-up visits of 14, 90, 180,and 365 days respectively. The human clinical subject had an IPSS of 10,8, 7, and 6 at follow-up visits of 30, 90, 180, and 365 daysrespectively.

The terms and expressions that have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theembodiments of the present invention. Thus, it should be understood thatalthough the present invention has been specifically disclosed byspecific embodiments and optional features, modification and variationof the concepts herein disclosed may be resorted to by those of ordinaryskill in the art, and that such modifications and variations areconsidered to be within the scope of embodiments of the presentinvention.

EXEMPLARY EMBODIMENTS

The following exemplary embodiments are provided, the numbering of whichis not to be construed as designating levels of importance:

Embodiment 1 provides a drug-coated balloon catheter for delivering atherapeutic agent to a target site of a body lumen stricture, theballoon catheter comprising:

an elongated balloon having a main diameter; and

a coating layer overlying an exterior surface of the balloon, whereinthe coating layer comprises one or more water-soluble additives and aninitial drug load of a therapeutic agent.

Embodiment 2 provides the balloon catheter of Embodiment 1, wherein theballoon comprises at least one neck section on the balloon comprising asmaller diameter than the main diameter when the balloon is inflated,the at least one neck section dividing the balloon into at least twomain sections each having a diameter.

Embodiment 3 provides the balloon catheter of Embodiment 2, wherein themain diameter is at least 13 mm, or at least 15 mm, or at least 20 mm,or at least 30 mm, or at least 35 mm.

Embodiment 4 provides the balloon catheter of Embodiment 2, wherein thediameter of the at least two main sections is equal to the main diameterof the elongated balloon, or the at least one neck section has adiameter that is about 5% to about 99% of the diameter of at least oneof the at least two main sections.

Embodiment 5 provides the balloon catheter of any one of Embodiments2-4, wherein the at least one neck section has a diameter that isindependently about 5 mm to about 35 mm.

Embodiment 6 provides the balloon catheter of any one of Embodiments2-5, wherein the diameter of the at least one neck section issubstantially static during inflation of the balloon.

Embodiment 7 provides the balloon catheter of any one of Embodiments2-6, wherein the at least one neck section comprises a substantiallynonelastic portion of the balloon, a reinforced portion of the balloon,or a combination thereof.

Embodiment 8 provides the balloon catheter of any one of Embodiments2-7, wherein the at least one neck section comprises an inelasticmaterial around a circumference of the neck section.

Embodiment 9 provides the balloon catheter of Embodiment 8, wherein theinelastic material comprises ultra high molecular weight polyethylene, anylon, a polyamide, or a combination thereof.

Embodiment 10 provides the balloon catheter of any one of the precedingEmbodiments, wherein the elongated balloon has a length of about 20 mmto about 160 mm.

Embodiment 11 provides the balloon catheter of any one of Embodiments2-10, wherein the diameter of the at least two main sections are about 5mm to about 45 mm.

Embodiment 12 provides the balloon catheter of any one of Embodiments2-11, wherein the at least one neck section is about 1% to about 50% ofthe balloon length.

Embodiment 13 provides the balloon catheter of any one of Embodiments2-12, wherein the at least one neck section is one neck section and theballoon is free of other neck sections.

Embodiment 14 provides the balloon catheter of any one of Embodiments2-12, wherein the at least one neck section is two neck sections and theballoon is free of other neck sections.

Embodiment 15 provides the balloon catheter of Embodiment 14, whereintwo neck sections have about the same diameter.

Embodiment 16 provides the balloon catheter of Embodiment 14, whereinone of the two neck sections have a smaller diameter than the other necksection.

Embodiment 17 provides the balloon catheter of any one of Embodiments14-16, wherein the two neck sections are symmetrically located withrespect to the center of the balloon length.

Embodiment 18 provides the balloon catheter of any one of Embodiments14-17, wherein the balloon catheter comprises three of the main sectionsseparated by the two neck sections.

Embodiment 19 provides the balloon catheter of any one of Embodiments2-18, wherein the at least one neck section is three neck sections,wherein the balloon is free of other neck sections.

Embodiment 20 provides the balloon catheter of Embodiment 19, whereinthe three neck sections are arranged to provide four of the mainsections separated by the three neck sections.

Embodiment 21 provides the balloon catheter of any one of the precedingEmbodiments, comprising a catheter shaft on a longitudinal end of theballoon, the catheter shaft comprising an interior lumen for delivery ofa gas, liquid, or a combination thereof, to the balloon interior.

Embodiment 22 provides the balloon catheter of any one of the precedingEmbodiments, comprising an atraumatic Coude tip.

Embodiment 23 provides the balloon catheter of any one of the precedingEmbodiments, wherein the therapeutic agent is chosen from paclitaxel,docetaxel, taxol, their analogues, rapamycin, sirolimus, everolimus,tacrolimus, mTOR inhibitors, their analogues, and combinations thereof.

Embodiment 24 provides the balloon catheter of any one of the precedingEmbodiments, wherein the water-soluble additive is chosen fromN-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

Embodiment 25 provides the balloon catheter of Embodiment 24, whereinthe water-soluble additive is chosen from pentaerythritol ethoxylate andpentaerythritol propoxylate, and combinations thereof.

Embodiment 26 provides the balloon catheter of any one of Embodiments 1to 23, wherein the water-soluble additive comprises a firstwater-soluble additive that is a surfactant.

Embodiment 27 provides the balloon catheter of Embodiment 26, whereinthe first water-soluble additive is a PEG sorbitan monolaurate, a PEGsorbitan monooleate, or a combination thereof.

Embodiment 28 provides the balloon catheter of any one of the precedingEmbodiments, wherein the water-soluble additive comprises a secondwater-soluble additive that is a chemical compound with one or moremoieties that are hydroxyl, amine, carbonyl, carboxyl, or ester.

Embodiment 29 provides the balloon catheter of Embodiment 28, whereinthe second water-soluble additive is sorbitol, sorbitan, xylitol,gluconolactone, or a combination thereof.

Embodiment 30 provides the balloon catheter of any one of the precedingEmbodiments, wherein after use the residual drug amount is about 70% orless of the initial drug load.

Embodiment 31 provides the balloon catheter of any one of the precedingEmbodiments, wherein the initial drug load is from about 1 microgram toabout 20 micrograms of the therapeutic agent per square millimeter ofthe balloon, measured when the balloon is at its nominal diameter.

Embodiment 32 provides the balloon catheter of any one of the precedingEmbodiments, wherein the initial drug load is from about 2 to about 6micrograms of the therapeutic agent per square millimeter of theballoon, measured when the balloon is at its nominal diameter.

Embodiment 33 provides the balloon catheter of any one of the precedingEmbodiments, wherein the body lumen is a nonvascular body lumen or avascular body lumen.

Embodiment 34 provides the balloon catheter of any one of the precedingEmbodiments, wherein the body lumen is a vascular lumen that is one ofcoronary arteries and peripheral arteries, or a nonvascular body lumenthat is one of esophagus, airways, sinus, trachea, colon, biliary tract,stomach, small intestine, duodenum, jejunum, ileum, rectum, largeintestine, urinary tract, prostate, urethra, and ureter.

Embodiment 35 provides the balloon catheter of any one of the precedingEmbodiments, wherein the ratio by weight of the therapeutic agent in thecoating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 0.05 to about 20.

Embodiment 36 provides the balloon catheter of any one of the precedingEmbodiments, wherein the ratio by weight of the therapeutic agent in thecoating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 0.5 to about 8.

Embodiment 37 provides the balloon catheter of any one of the precedingEmbodiments, wherein the ratio by weight of the therapeutic agent in thecoating layer to the total weight of the one or more water-solubleadditives in the coating layer is from about 2 to about 6.

Embodiment 38 provides the balloon catheter of any one of the precedingEmbodiments, wherein the balloon catheter has a stretch ratio of about1.0 to about 20.

Embodiment 39 provides the balloon catheter of any one of the precedingEmbodiments wherein the balloon catheter further comprises a sheathcovering the elongated balloon.

Embodiment 40 provides the balloon catheter of any one of the precedingEmbodiments, wherein the balloon catheter is for delivering thetherapeutic agent to the target site of the body lumen after the bodylumen has been flushed with water, saline solution, or a water solutioncomprising at least one water soluble additive.

Embodiment 41 provides a method for treating a body lumen stricture, themethod comprising:

inserting a balloon catheter into a target site in the body lumenstricture, the balloon catheter comprising

-   -   an elongated balloon, and    -   a coating layer overlying an exterior surface of the balloon,        wherein the coating layer comprises one or more water-soluble        additives and an initial drug load of a therapeutic agent;

inflating the balloon until the coating layer contacts walls of the bodylumen at the target site and the balloon achieves an inflated balloondiameter for an inflation period, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c);

deflating the balloon after the inflation period; and

withdrawing the balloon catheter from the body lumen.

Embodiment 42 provides the method of Embodiment 41, wherein the ballooncatheter comprises an elongated balloon having a proximal waist, adistal waist, a main body diameter and at least one neck section on theballoon comprising a smaller diameter than the main diameter when theballoon is inflated, the at least one neck section dividing the ballooninto at least two main sections each having a diameter.

Embodiment 43 provides the method of Embodiment 42, wherein the diameterof the at least two main sections is equal to the main diameter of theelongated balloon.

Embodiment 44 provides the method of any one of Embodiments 41-43,further comprising, prior to the insertion of the balloon to the targetsite, flushing the body lumen with water, saline solution, or a watersolution comprising at least one water soluble additive.

Embodiment 45 provides the method of any one of Embodiments 42 to 44,wherein the body lumen is a prostate, wherein inserting the ballooncatheter comprises positioning one of the balloon catheter main sectionsin the prostate and positioning a second main section of the ballooncatheter in the bladder.

Embodiment 46 provides the method of Embodiment 45, wherein theinserting comprises positioning the at least one neck section of theballoon in the bladder neck.

Embodiment 47 provides the method of any one of Embodiments 41 to 46,wherein the inflating comprises increasing pressure within the balloonat a rate of about 0.1 to about 10 atm/minute.

Embodiment 48 provides the method of any one of Embodiments 41 to 47,wherein the inflating comprises observing pressure within the balloon.

Embodiment 49 provides the method of any one of Embodiments 41 to 48,wherein the inflating comprises inflating the balloon to a firstpressure, allowing pressure within the balloon to stabilize whilemaintaining the first pressure in the balloon for a stabilizationperiod, then resuming increasing pressure in the balloon until a desiredinflation diameter is achieved.

Embodiment 50 provides the method of any one of Embodiments 41 to 49,wherein the inflation period is from about 0.1 minutes to about 7 days,0.1 minutes to about 1 day, about 0.1 to about 10 minutes, or about 1 toabout 10 minutes.

Embodiment 51 provides the method of any one of Embodiments 41 to 50,wherein the method is a method of treating a vascular lumen, anonvascular lumen, a coronary artery, a peripheral artery, a benignprostatic hyperplasia (BPH) stricture, a urethra, a ureter, a prostate,an esophagus, a stricture in a stent, a biliary tract, a stomach, asmall intestine, a duodenum, a jejunum, an ileum, a colon, a rectum, alarge intestine, a sinus, asthma, or chronic obstructive pulmonarydisease (COPD).

Embodiment 52 provides the method of any one of Embodiments 41 to 51,wherein the method is a method of splitting an enlarged prostate orcreating a commissurotomy for treating benign prostate hyperplasia.

Embodiment 53 provides the method of any one of Embodiments 41 to 52,wherein the stricture in the body lumen is one of urethral strictures, abenign prostatic hyperplasia (BPH) stricture, a ureteral stricture, anesophageal stricture, a stricture in a stent, a sinus stricture, abiliary tract stricture, stomach strictures, small intestine strictures,duodenum strictures, jejunum strictures, ileum strictures, colonstrictures, rectum strictures, large intestine strictures, prostaticcancer strictures, and airway strictures.

Embodiment 54 provides the method of Embodiment 53, wherein the methodis a method of treating benign prostatic hyperplasia, prostate cancer,or a combination thereof, wherein the body lumen is a prostate.

Embodiment 55 provides the method of any one of Embodiments 41 to 54,wherein the one or more water-soluble additives promote rapid release ofthe therapeutic agent from the balloon at the target site during theinflation period.

Embodiment 56 provides the method of any one of Embodiments 41 to 55,wherein the balloon has thereon a residual drug amount after thewithdrawing.

Embodiment 57 provides the method of Embodiment 56, wherein the balloonhas thereon a residual drug amount of less than about 70% of the initialdrug load after the withdrawing.

Embodiment 58 provides the method of any one of Embodiments 41 to 57,wherein the balloon catheter further comprises a sheath covering theballoon and wherein the sheath is removed from the balloon prior toinflating the balloon

Embodiment 59 provides the method of any one of Embodiments 41 to 57,wherein a scope is used to properly position the balloon catheter.

Embodiment 60 provides the method of Embodiment 59, wherein the scope isan endoscope, enteroscope, colonoscope, sigmoidoscope, rectoscope,anoscope, rhinoscope, bronchoscope, or cystoscope.

Embodiment 61 provides the method of any one of Embodiments 59 to 60,wherein the balloon catheter is positioned within the lumen of thescope.

Embodiment 62 provides the method of any one of Embodiments 59 to 60,wherein the balloon catheter is positioned side by side with the scopewhen in the body lumen.

Embodiment 63 provides the method of any one of Embodiments 42 to 62,wherein the body lumen is the prostatic urethra and wherein wheninserting the balloon catheter to the target site a scope is used toposition the proximal waist of the balloon catheter within the externalsphincter of the prostatic urethra.

Embodiment 64 provides the method of any one of Embodiments 41 to 63,further comprising inserting a predilation balloon into the body lumento the target site, inflating the predilation balloon, and removing thepredilation balloon prior to inserting the drug coated balloon catheter.

Embodiment 65 provides the method of any one of Embodiments 41 to 64,wherein the balloon catheter has a ratio of inflated balloon diameter tonormative body lumen diameter at the target site of 1.0, 1.1, 1.2, or1.31 to 10, or the balloon catheter has a stretch ratio of the nominalballoon diameter to the normative body lumen diameter at the target siteof 1.0, 1.1, 1.2, or 1.31 to 10, or a combination thereof.

Embodiment 66 provides a method for treating a body lumen stricture, themethod comprising:

inserting a scope into a body lumen stricture;

inserting a balloon catheter with a drug coating into the body lumenstricture;

inflating to the balloon catheter to an initial pressure of between 0.5atm and 1.5 atm and maintaining the initial pressure until the pressureno longer drops;

inflating to a next higher pressure at least 0.5 atm to 1.5 atm abovethe initial pressure and maintaining the next higher pressure until thepressure inside the balloon no longer drops;

repeating the inflating to the next higher pressure and the maintaininguntil the lumen is dilated to a desired diameter;

keeping the balloon inflated for 1 minute to 7 days to release the druginto tissue and to prevent bleeding;

deflating the balloon catheter; and

withdrawing the scope and balloon catheter from the body lumen.

Embodiment 67 provides the method of Embodiment 66, wherein the scopeand balloon catheter are positioned side by side in the body lumen;

Embodiment 68 provides the method of Embodiment 66, wherein the ballooncatheter is loaded into the scope prior to inserting into the bodylumen.

Embodiment 69 provides the method of any one of Embodiments 66 to 68,wherein the desired diameter of the body lumen is 1.0 to 20 times anormative diameter of the body lumen at the location of treatment.

Embodiment 70 provides the method of any one of Embodiments 66 to 69,wherein the balloon catheter further comprises a sheath covering theballoon and wherein the sheath is removed from the balloon prior toinflating the balloon to an initial pressure.

Embodiment 71 provides a method for treatment of a body lumen stricturecomprising:

inserting a flexible scope to the body lumen stricture;

inserting a balloon catheter in the body lumen stricture side by sidewith the scope;

flushing with water, saline, or a solution of a water-soluble additiveprior to, during, or after inserting the balloon catheter into thestricture;

inflating to an initial pressure between 0.5 atm and 1.5 atm andmaintaining the initial pressure until the pressure no longer drops;

inflating to a higher pressure 0.5 atm to 1.5 atm above the initialpressure and maintaining the higher pressure until the pressure nolonger drops;

repeating the inflating to the higher pressure and the maintaining untilthe tissue of body lumen yields;

keeping the balloon inflated for 1 minute to 7 days to release the druginto tissue and to prevent bleeding;

deflating the balloon catheter; and

withdrawing the scope and the balloon catheter assembly from the bodylumen.

Embodiment 72 provides a method of increasing Q_(max) comprising:

inserting a balloon catheter into a target site in a urinary tractstricture, the balloon catheter comprising an elongated balloon and acoating layer overlying an exterior surface of the balloon, wherein thecoating layer comprises one or more water-soluble additives and aninitial drug load of a therapeutic agent;

inflating the balloon until the coating layer contacts the walls of theurinary tract stricture for an inflation period, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        urinary tract diameter at the target site is about 1.0 to about        20, or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative urinary tract diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c);

deflating the balloon after the inflation period; and

withdrawing the balloon catheter from the urinary tract;

wherein the method increases Q_(max) to a minimum of 15 mL/s.

Embodiment 73 provides the method of Embodiment 72, wherein the targetsite is a urethral stricture.

Embodiment 74 provides the method of Embodiment 73, wherein the ratio ofthe inflated balloon diameter to a normative diameter of the body lumenat the target site is about 1.31 to about 20, or wherein the stretchratio of the nominal diameter of the balloon catheter to a normativebody lumen diameter at the target site is about 1.31 to about 20, or acombination thereof.

Embodiment 75 provides the method of Embodiment 72, wherein the targetsite is the prostate.

Embodiment 76 provides the method of Embodiment 75, wherein theelongated balloon has a main diameter and at least one neck sectiondividing the balloon into at least two main sections, the neck sectioncomprising a smaller diameter than the main diameter of the balloon whenthe balloon is inflated.

Embodiment 77 provides the method of Embodiment 76, wherein the at leasttwo main sections of the balloon each have a diameter equal to the mainsection of the balloon when the balloon is inflated.

Embodiment 78 provides the method of any one of Embodiments 72-77,wherein Q_(max) is still above 15 mL/s six months after the initialtreatment.

Embodiment 79 provides the method of any one of Embodiments 72-78,wherein Q_(max) is still above 15 mL/s twelve months after the initialtreatment.

Embodiment 80 provides a method of decreasing International ProstateSymptom Score (IPSS) comprising:

inserting a balloon catheter into a target site in a urinary tractstricture, the balloon catheter comprising an elongated balloon and acoating layer overlying an exterior surface of the balloon, wherein thecoating layer comprises one or more water-soluble additives and aninitial drug load of a therapeutic agent;

inflating the balloon until the coating layer contacts the walls of theurinary tract stricture for an inflation period, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter and the nominal pressure is less than the        inflation pressure, or    -   d) a combination of (a), (b), and (c);

deflating the balloon after the inflation period; and

withdrawing the balloon catheter from the urinary tract stricture;

wherein the method decreases the IPSS to 14 or less.

Embodiment 81 provides the method of Embodiment 80, wherein the targetsite is a urethral stricture.

Embodiment 82 provides the method of Embodiment 81, wherein the ratio ofthe inflated balloon diameter to the normative diameter of the bodylumen at the target site is about 1.31 to about 20, or wherein thestretch ratio of the minimal diameter of the balloon catheter to anormative body diameter at the target site is about 1.31 to about 20, ora combination thereof.

Embodiment 83 provides the method of Embodiment 80, wherein the targetsite is the prostate.

Embodiment 84 provides the method of Embodiment 83, wherein theelongated balloon has a main diameter and at least one neck sectiondividing the balloon into at least two main sections, the neck sectioncomprising a smaller diameter than the main diameter of the balloon whenthe balloon is inflated.

Embodiment 85 provides the method of Embodiment 84, wherein the at leasttwo main sections of the balloon each have a diameter equal to the mainsection of the balloon when the balloon is inflated.

Embodiment 86 provides the method of any one of Embodiments 80 to 85,wherein IPSS is still below 14 six months after the initial treatment.

Embodiment 87 provides the method of any one of Embodiments 80 to 86,wherein IPSS is still below 14 twelve months after the initialtreatment.

Embodiment 88 provides the method of any one of Embodiments 72-87,wherein the therapeutic agent is chosen from paclitaxel, docetaxel,taxol, their analogues, rapamycin, sirolimus, everolimus, tacrolimus,mTOR inhibitors, their analogues, and combinations thereof.

Embodiment 89 provides the method of any one of Embodiments 72-88,wherein the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

Embodiment 90 provides the method of Embodiment 89, wherein thewater-soluble additive is chosen from pentaerythritol ethoxylate andpentaerythritol propoxylate, and combinations thereof.

Embodiment 91 provides the method of any one of Embodiments 72 to 90,wherein the water-soluble additive comprises a first water-solubleadditive that is a surfactant.

Embodiment 92 provides the method of Embodiment 91, wherein the firstwater-soluble additive is a PEG sorbitan monolaurate, a PEG sorbitanmonooleate, or a combination thereof.

Embodiment 93 provides the method of any one of Embodiments 72-92,wherein the water-soluble additive comprises a second water-solubleadditive that is a chemical compound with one or more moieties that arehydroxyl, amine, carbonyl, carboxyl, or ester.

Embodiment 94 provides the method of any one of Embodiments 72-93,wherein the urethra is flushed with water, saline, or a solution of awater-soluble additive prior to inserting the balloon catheter into theurethra.

Embodiment 95 provides the method any one of Embodiments 72-94, whereinthe balloon is wetted with water, saline, or a solution of awater-soluble additive prior to inserting the balloon catheter into theurethra.

Embodiment 96 provides the method of any one of Embodiments 72-95,wherein the balloon is loaded with about 2 to about 6 micrograms of thetherapeutic agent per square millimeter of the balloon, measured whenthe balloon is at its nominal diameter.

Embodiment 97 provides the method of any Embodiments 72-96, wherein ascope is used to properly position the balloon catheter, wherein alocation balloon (e.g., in the bladder) is used to properly position theballoon catheter, or a combination thereof.

Embodiment 98 provides the method of Embodiment 97, wherein the scope isone of an endoscope, enteroscope, colonoscope, sigmoidoscope,rectoscope, anoscope, rhinoscope, bronchoscope, or cystoscope.

Embodiment 99 provides the method of any one of Embodiments 72-98,wherein the balloon catheter is positioned within the lumen of thescope.

Embodiment 100 provides the method of any one of Embodiments 72 to 99,wherein the balloon catheter is positioned side by side with the scopewhen in the body lumen.

Embodiment 101 provides the method of any one of Embodiments 72-100,wherein the body lumen is the prostatic urethra and wherein wheninserting the balloon catheter to the target site a scope is used toposition the proximal waist of the balloon catheter within the externalsphincter of the prostatic urethra.

Embodiment 102 provides the method of any one of Embodiments 72-101,further comprising inserting a predilation balloon into the body lumento the target site, inflating the predilation balloon, and removing thepredilation balloon prior to inserting the drug coated balloon catheter.

Embodiment 103 provides the method of any one of Embodiments 72-102,wherein the balloon catheter is inflated to a ratio of inflated balloondiameter to the normative diameter of the body lumen at the target siteof 1.31 to 15, or wherein the balloon catheter has a stretch ratio ofthe nominal balloon diameter to the normative diameter of the body lumenat the target site of 1.31 to 15, or a combination thereof.

Embodiment 104 provides the method of any one of Embodiments 41-103,further comprising performing a direct vison internal urethrotomy (DVIU)on the body lumen prior to treating the body lumen with the drug coatedballoon catheter.

Embodiment 105 provides a method of splitting an enlarged prostate orcreating a commissurotomy for treating benign prostate hyperplasiacomprising:

inserting a drug coated balloon catheter sheath assembly and a scope;

putting the scope and balloon catheter side by side near the externalsphincter;

removing the sheath from over the balloon and slowly inflating until thepressure drops, the prostatic tissue yields and the commissurotomy iscreated;

increasing the pressure further to rated burst pressure to dilate theprostate more;

keeping the balloon inflated for 1 minute to 7 days to release the druginto tissue and to prevent bleeding;

deflating the balloon catheter and covering the balloon with the sheath;and

withdrawing the scope and balloon catheter assembly from the body lumen,wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c).

Embodiment 106 provides a method of splitting an enlarged prostate orcreating a commissurotomy for treating benign prostate hyperplasiacomprising:

inserting an uncoated balloon catheter sheath assembly and a scope;

putting the scope and balloon catheter side by side near the externalsphincter;

removing the sheath from over the balloon and slowly inflating until thepressure drops, the prostatic tissue yields and the commissurotomy iscreated;

increasing the pressure further to rated burst pressure to dilate theprostate more;

keeping the balloon inflated for 1 minute to 7 days to prevent bleeding;

deflating the uncoated balloon catheter and covering the balloon withthe sheath;

withdrawing the scope and uncoated balloon catheter assembly from thebody lumen;

inserting a drug coated balloon catheter sheath assembly and the scope;

putting the scope and drug coated balloon catheter side by side near theexternal sphincter;

removing the sheath from over the drug coated balloon and slowlyinflating to rated burst pressure to dilate the prostate more; and

keeping the balloon inflated for 1 minute to 7 days to release the druginto tissue and to prevent bleeding, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c).

Embodiment 107 provides a method for treating benign prostatehyperplasia, the method comprising:

inserting a balloon catheter into a target site in the prostate, theballoon catheter comprising a coating layer overlying an exteriorsurface of the balloon, wherein the coating layer comprises one or morewater-soluble additives and an initial drug load of a therapeutic agent;

inflating the balloon until the coating layer contacts walls of the bodylumen at the target site and the balloon achieves an inflated balloondiameter for an inflation period, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c);

deflating the balloon after the inflation period; and

withdrawing the balloon catheter from the body lumen;

wherein the prostatic urethra and prostate is split and the prostaticurethra diameter is at least 12 mm, and wherein the inflated diameter ofthe balloon catheter is at least 25 mm.

Embodiment 108 provides a method for treating a urethral stricture, themethod comprising:

-   -   inserting a balloon catheter into a target site in the urethra,        the balloon catheter comprising a coating layer overlying an        exterior surface of the balloon, wherein the coating layer        comprises one or more water-soluble additives and an initial        drug load of a therapeutic agent; wherein the therapeutic agent        is paclitaxel, docetaxel, taxol, their analogues, rapamycin,        sirolimus, everolimus, tacrolimus, MTOR inhibitors, their        analogues, and combinations thereof and the water-soluble        additives is at least one of N-acetylglucosamine,        N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine,        N-octanoyl-N-methyl glutamine, C6-ceramide, dihydro-C6-ceramide,        cerabroside, sphingomyelin, galaclocerebrosides,        lactocerebrosides, N-acetyl-D-sphingosine,        N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,        N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,        N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8        caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG        caprate, PEG caproate, glyceryl monocaprylate, glyceryl        monocaprate, glyceryl monocaproate, monolaurin, monocaprin,        monocaprylin, monomyristin, monopalmitolein, monoolein,        creatine, creatinine, agmatine, citrulline, guanidine,        sucralose, aspartame, hypoxanthine, theobromine, theophylline,        adenine, uracil, uridine, guanine, thymine, thymidine, xanthine,        xanthosine, xanthosine monophosphate, caffeine, allantoin,        (2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea,        pentaerythritol ethoxylate, pentaerythritol propoxylate,        pentaerythritol propoxylate/ethoxylate, glycerol ethoxylate,        glycerol propoxylate, trimethylolpropane ethoxylate,        pentaerythritol, dipentaerythritol, crown ether, 18-crown-6,        15-crown-5, 12-crown-4, and combinations thereof;

inflating the balloon until the coating layer contacts walls of the bodylumen at the target site and the balloon achieves an inflated balloondiameter for an inflation period, wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c);

deflating the balloon after the inflation period; and

withdrawing the balloon catheter from the body lumen;

wherein the urethra diameter after dilation is at least 6.7 mm, and theinflated diameter of the balloon catheter is at least 7 mm.

Embodiment 109 provides a balloon catheter for treating a urethralstricture comprising:

a coating layer overlying an exterior surface of the balloon, whereinthe coating layer comprises one or more water-soluble additives and aninitial drug load of a therapeutic agent; wherein the therapeutic agentis paclitaxel, docetaxel, taxol, their analogues, rapamycin, sirolimus,everolimus, tacrolimus, MTOR inhibitors, their analogues, andcombinations thereof and the water-soluble additives is at least one ofN-acetylglucosamine, N-octyl-D-gluconamide,N-nonanoyl-N-methylglycamine, N-octanoyl-N-methyl glutamine,C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof;

wherein

-   -   after treatment Q_(max) is at least 15 mL per second and IPSS is        no more than 14,    -   the urethra diameter after dilation is at least 6.7 mm, and    -   the inflated diameter of the balloon catheter is at least 7 mm;        and

wherein

-   -   a) the ratio of the inflated balloon diameter to a normative        body lumen diameter at the target site is about 1.0 to about 20,        or    -   b) the inflating comprises inflating the balloon to a pressure        equal to or greater than a nominal pressure of the balloon        catheter, and the stretch ratio of a nominal diameter of the        balloon catheter to a normative body lumen diameter at the        target site is about 1.0 to about 20, or    -   c) the inflating comprises inflating to a pressure greater than        the nominal pressure of the balloon catheter, and the nominal        diameter of the balloon catheter is less than the inflated        balloon diameter, or    -   d) a combination of (a), (b), and (c).

Embodiment 110 provides a method of forming a balloon, the methodcomprising

placing a tube comprising balloon material into a balloon mold whereinthe balloon mold has a shape comprising a proximal cone, at least onemain body section, at least one neck section having a diameter less thanthe at least one main body section, another at least one main bodysection, and a distal cone;

pressurizing the interior of the balloon material tube; and

expanding the balloon material tube into contact with the interior ofthe mold.

Embodiment 111 provides the method of Embodiment 110, furthercomprising, assembling the balloon into a balloon catheter.

Embodiment 112 provides the method of Embodiment 111, wherein theballoon catheter is chosen from fixed wire catheters, moveable wirecatheters, over the wire catheters, and rapid exchange catheters.

Embodiment 113 provides the method of any one of Embodiments 110-112,wherein a neck reinforcement is added to a neck section.

Embodiment 114 provides the method of any one of Embodiments 110-113,further comprising coating the balloon of the balloon catheter with atherapeutic agent and at least one water soluble additive.

Embodiment 115 provides the method of any one of Embodiments 110-114,wherein the therapeutic agent is chosen from paclitaxel, docetaxel,taxol, their analogues, rapamycin, sirolimus, everolimus, tacrolimus,mTOR inhibitors, their analogues, and combinations thereof.

Embodiment 116 provides the method of any one of Embodiments 110-115,wherein the water-soluble additive is chosen from N-acetylglucosamine,N-octyl-D-gluconamide, N-nonanoyl-N-methylglycamine, N-octanoyl-N-methylglutamine, C6-ceramide, dihydro-C6-ceramide, cerabroside, sphingomyelin,galaclocerebrosides, lactocerebrosides, N-acetyl-D-sphingosine,N-hexanoyl-D-sphingosine, N-octonoyl-D-sphingosine,N-lauroyl-D-sphingosine, N-palmitoyl-D-sphingosine,N-oleoyl-D-sphingosine, PEG caprylic/capric diglycerides, PEG8caprylic/capric glycerides, PEG caprylate, PEG8 caprylate, PEG caprate,PEG caproate, glyceryl monocaprylate, glyceryl monocaprate, glycerylmonocaproate, monolaurin, monocaprin, monocaprylin, monomyristin,monopalmitolein, monoolein, creatine, creatinine, agmatine, citrulline,guanidine, sucralose, aspartame, hypoxanthine, theobromine,theophylline, adenine, uracil, uridine, guanine, thymine, thymidine,xanthine, xanthosine, xanthosine monophosphate, caffeine, allantoin,(2-hydroxyethyl)urea, N,N′-bis(hydroxymethyl)urea, pentaerythritolethoxylate, pentaerythritol propoxylate, pentaerythritolpropoxylate/ethoxylate, glycerol ethoxylate, glycerol propoxylate,trimethylolpropane ethoxylate, pentaerythritol, dipentaerythritol, crownether, 18-crown-6, 15-crown-5, 12-crown-4, and combinations thereof.

Embodiment 117 provides the balloon catheter of Embodiment 116, whereinthe water-soluble additive is chosen from pentaerythritol ethoxylate andpentaerythritol propoxylate, and combinations thereof.

Embodiment 118 provides the balloon catheter of any one of Embodiments110-117, wherein the water-soluble additive comprises a secondwater-soluble additive that is a chemical compound with one or moremoieties that are hydroxyl, amine, carbonyl, carboxyl, or ester.

Embodiment 119 provides the balloon catheter or method of any one or anycombination of Embodiments 1-118 optionally configured such that allelements or options recited are available to use or select from.

What is claimed is:
 1. A drug-coated balloon catheter comprising: anelongated balloon having a nominal diameter of 4 mm to 50 mm and alength of 20 mm to 160 mm; and a coating layer overlaying an exteriorsurface of the balloon, the coating layer comprising an initial drugload of a therapeutic agent, the therapeutic agent comprisingpaclitaxel, a paclitaxel analogue, docetaxel, a docetaxel analogue,taxol, a taxol analogue, rapamycin, a rapamycin analogue, sirolimus, asirolimus analogue, everolimus, an everolimus analogue, tacrolimus, atacrolimus analogue, mammalian target of rapamycin (mTOR) inhibitors, anmTOR inhibitor analogue, or a combination thereof, and one or moreadditives, wherein a ratio of the therapeutic agent to the one or moreadditives in the coating layer is 0.1 to 10; wherein a soaking procedurefor treating a target site in a body lumen with the drug-coated ballooncatheter is sufficient for the coating layer to release 37 wt % to 97 wt% of the initial drug load of the therapeutic agent from the coatinglayer, wherein the soaking procedure consists of passing the drug-coatedballoon catheter through an introducer sheath into a cylindrical vessel,the cylindrical vessel comprising 0.9% saline at 37° C., soaking thedrug-coated balloon catheter in the saline in the cylindrical vessel for1 minute, inflating the drug-coated balloon catheter for 1 minute, andwithdrawing the drug-coated balloon catheter from the cylinder.
 2. Thedrug-coated balloon catheter of claim 1, wherein the initial drug loadof the therapeutic agent is from 1 microgram to 20 micrograms per squaremillimeter of the balloon at the nominal diameter of the balloon.
 3. Thedrug-coated balloon catheter of claim 1, wherein a ratio by weight ofthe therapeutic agent to the total weight of the one or more additivesin the coating layer is from 0.1 to
 5. 4. The drug-coated ballooncatheter of claim 1, wherein a ratio by weight of the therapeutic agentto the total weight of the one or more additives in the coating layer isfrom 2 to
 6. 5. The drug-coated balloon catheter of claim 1, wherein theinitial drug load of the therapeutic agent is from 1 microgram to 20micrograms per square millimeter of the balloon at the nominal diameterof the balloon.
 6. The drug-coated balloon catheter of claim 1, whereinthe one or more additives in the coating layer comprise one or morewater-soluble additives.
 7. The drug-coated balloon catheter of claim 1,wherein the one or more additives in the coating layer comprise one ormore surfactants.
 8. The drug-coated balloon catheter of claim 7,wherein the surfactant is a nonionic, anionic, cationic, or zwitterionicsurfactant.
 9. The drug-coated balloon catheter of claim 8, wherein thesurfactant is a quaternary ammonium salt, a fatty acid salt, a bilesalt, benzalkonium chloride, benzethonium chloride, cetylpyridiniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, edrophonium chloride, domiphenbromide, dialkylester of sodium sulfonsuccinic acid, sodium dioctylsulfosuccinate, sodium cholate, sodium taurocholate, or a combinationthereof.
 10. The drug-coated balloon catheter of claim 1, wherein theone or more additives in the coating layer comprise one or more sterolsand/or sterol derivatives.
 11. The drug-coated balloon catheter of claim10, wherein the one or more sterols and/or sterol derivatives comprisePEG-24 cholesterol ether.
 12. The drug-coated balloon catheter of claim1, wherein the one or more additives in the coating layer comprise oneor more polymers.
 13. The drug-coated balloon catheter of claim 1,wherein the one or more additives in the coating layer comprise apolymer, and a sterol and/or sterol derivative.
 14. The drug-coatedballoon catheter of claim 1, wherein the one or more additives in thecoating layer comprise a polymer and a surfactant.
 15. The drug-coatedballoon catheter of claim 1, wherein the drug-coated balloon catheterfurther comprises an adherent layer between the exterior surface of theballoon and the coating layer, wherein the adherent layer improves theadherence of the coating layer to the exterior surface of the balloon.16. A drug-coated balloon catheter comprising: an elongated balloonhaving a nominal diameter of 4 mm to 50 mm and a length of 20 mm to 160mm; and a coating layer overlaying an exterior surface of the balloon,the coating layer comprising an initial drug load of a therapeuticagent, the therapeutic agent comprising paclitaxel, a paclitaxelanalogue, docetaxel, a docetaxel analogue, taxol, a taxol analogue,rapamycin, a rapamycin analogue, sirolimus, a sirolimus analogue,everolimus, an everolimus analogue, tacrolimus, a tacrolimus analogue,mammalian target of rapamycin (mTOR) inhibitors, an mTOR inhibitoranalogue, or a combination thereof, and one or more additives, wherein aratio of the therapeutic agent to the one or more additives in thecoating layer is 0.1 to 10; wherein a treatment procedure for treating atarget site in a body lumen with the drug-coated balloon catheter issufficient for the coating layer to release more than 30 wt % of theinitial drug load of the therapeutic agent from the coating layer to thetarget site in the body lumen, wherein the treatment procedure consistsof flushing the target site in the body lumen with a flushing mediacomprising water, saline solution, or a water solution comprising atleast one water-soluble additive, inserting the drug-coated ballooncatheter into the body lumen such that the drug-coated balloon catheteris at the target site in the body lumen, holding the drug-coated ballooncatheter in position at the target site for a soaking period of at least1 minute prior to inflation to hydrate the coating layer in the flushingmedia, inflating the drug-coated balloon catheter to contact walls ofthe body lumen at the target site with the coating layer for aninflation period of 0.1 minute to 10 minutes, deflating the drug-coatedballoon catheter, and withdrawing the drug-coated balloon catheter fromthe target site.
 17. The drug-coated balloon catheter of claim 16,wherein the treatment procedure is sufficient for the coating layer torelease 37%-97% of the initial drug load to the target site in the bodylumen.
 18. The drug-coated balloon catheter of claim 16, wherein a ratioby weight of the therapeutic agent to the total weight of the one ormore additives in the coating layer is from 0.1 to
 5. 19. Thedrug-coated balloon catheter of claim 16, wherein the body lumencomprises a vascular lumen, a nonvascular lumen, a coronary artery, aperipheral artery, a prostatic urethra, a urethra, a ureter, anesophagus, a biliary tract, a stomach, a small intestine, a duodenum, ajejunum, an ileum, a colon, a rectum, a large intestine, a sinus, or abronchial airway.
 20. The drug-coated balloon catheter of claim 16,wherein the initial drug load of the therapeutic agent is from 1microgram to 20 micrograms per square millimeter of the balloon at thenominal diameter of the balloon.
 21. A drug-coated balloon cathetercomprising: an elongated balloon having a nominal diameter of 4 mm to 50mm and a length of 20 mm to 160 mm; and a coating layer overlaying anexterior surface of the balloon, the coating layer comprising an initialdrug load of a therapeutic agent of 1 micrograms to 20 micrograms of atherapeutic agent per square millimeter of the balloon at the nominaldiameter of the balloon, the therapeutic agent comprising paclitaxel, apaclitaxel analogue, docetaxel, a docetaxel analogue, taxol, a taxolanalogue, rapamycin, a rapamycin analogue, sirolimus, a sirolimusanalogue, everolimus, an everolimus analogue, tacrolimus, a tacrolimusanalogue, mammalian target of rapamycin (mTOR) inhibitors, an mTORinhibitor analogue, or a combination thereof, and one or more additives,wherein a ratio of the therapeutic agent to the one or more additives inthe coating layer is 0.1 to 10; wherein a treatment procedure fortreating a target site in a body lumen with the drug-coated ballooncatheter is sufficient for the coating layer to release the therapeuticagent from the coating layer into body lumen tissue at the target sitesuch that the body lumen tissue at the target site have a concentrationof the therapeutic agent of 0.083 μg/g to 582 μg/g at 1 day, wherein thetreatment procedure consists of flushing the target site in the bodylumen with a flushing media comprising water, saline solution, or awater solution comprising at least one water-soluble additive, insertingthe drug-coated balloon catheter into the body lumen such that thedrug-coated balloon catheter is at the target site in the body lumen,holding the drug-coated balloon catheter in position at the target sitefor a soaking period of at least 1 minute prior to inflation to hydratethe coating layer in the flushing media, inflating the drug-coatedballoon catheter to contact walls of the body lumen at the target sitewith the coating layer for an inflation period of 0.1 minute to 10minutes, deflating the drug-coated balloon catheter, and withdrawing thedrug-coated balloon catheter from the target site.
 22. The drug-coatedballoon catheter of claim 21, wherein the treatment procedure issufficient for the coating layer to release the therapeutic agent fromthe coating layer into body lumen tissue at the target site such thatthe body lumen tissue at the target site have a concentration of thetherapeutic agent of 0.003 μg/g to 62 μg/g at 7 days.
 23. Thedrug-coated balloon catheter of claim 21, wherein the treatmentprocedure is sufficient for the coating layer to release the therapeuticagent from the coating layer into body lumen tissue at the target sitesuch that the body lumen tissue at the target site have a concentrationof the therapeutic agent of 0.025 μg/g to 33 μg/g at 28 days.
 24. Thedrug-coated balloon catheter of claim 21, wherein a ratio by weight ofthe therapeutic agent to the total weight of the one or more additivesin the coating layer is from 0.1 to
 5. 25. A drug-coated ballooncatheter comprising: an elongated balloon having a nominal diameter of 4mm to 50 mm and a length of 20 mm to 160 mm; and a coating layeroverlaying an exterior surface of the balloon, the coating layercomprising an initial drug load of a therapeutic agent, the therapeuticagent comprising paclitaxel, a paclitaxel analogue, docetaxel, adocetaxel analogue, taxol, a taxol analogue, rapamycin, a rapamycinanalogue, sirolimus, a sirolimus analogue, everolimus, an everolimusanalogue, tacrolimus, a tacrolimus analogue, mammalian target ofrapamycin (mTOR) inhibitors, an mTOR inhibitor analogue, or acombination thereof, and one or more additives, wherein a ratio of thetherapeutic agent to the one or more additives in the coating layer is0.1 to 10; wherein a treatment procedure for treating a target site in abody lumen with the drug-coated balloon catheter is sufficient for thecoating layer to release 0.1% to 25% of the initial drug load of thetherapeutic agent from the coating layer to a body lumen wall at thetarget site in the body lumen, wherein the treatment procedure consistsof flushing the target site in the body lumen with a flushing mediacomprising water, saline solution, or a water solution comprising atleast one water-soluble additive, inserting the drug-coated ballooncatheter into the body lumen such that the drug-coated balloon catheteris at the target site in the body lumen, holding the drug-coated ballooncatheter in position at the target site for a soaking period of at least1 minute prior to inflation to hydrate the coating layer in the flushingmedia, inflating the drug-coated balloon catheter to contact the bodylumen wall at the target site with the coating layer for an inflationperiod of 0.1 minute to 10 minutes, deflating the drug-coated ballooncatheter, and withdrawing the drug-coated balloon catheter from thetarget site.
 26. The drug-coated balloon catheter of claim 25, whereinthe initial drug load of the therapeutic agent is from 1 microgram to 20micrograms per square millimeter of the balloon at the nominal diameterof the balloon.
 27. The drug-coated balloon catheter of claim 25,wherein a ratio by weight of the therapeutic agent to the total weightof the one or more additives in the coating layer is from 0.1 to 5.